RU2829466C2 - Methods of treating cholestasis - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical industry, namely to use of maralixibate chloride. Use of maralixibate chloride for the treatment of Alajil syndrome (ALGS) in a paediatric subject in need of such treatment, in amount of 400 to 800 mcg/kg/day, at which the subject experiences itching before the introduction of maralixibate chloride. Use of maralixibate chloride for the treatment of Alajil syndrome (ALGS) in a paediatric subject in need of such treatment in amount of 800 mcg/kg/day, in which the subject experiences itching prior to administration of maralixibate chloride. Use of maralixibate chloride for treating Alajil's syndrome (ALGS) in a paediatric subject in need of such treatment in amount of 400 mcg/kg/day, in which the subject experiences itching before the introduction of maralixibate chloride.

EFFECT: use of the group of inventions provides the treatment of Alajil syndrome, as well as reduced severity of itching.

12 cl, 36 dwg, 19 tbl, 4 ex

Description

Link to related applications

[0001] This application claims priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Nos. 62/804,523, filed February 12, 2019, 62/863,904, filed June 20, 2019, 62/908,431, filed September 30, 2019, and 62/932,015, filed November 7, 2019, the entirety of which is incorporated herein by reference for all purposes.

Field of technology to which the present invention relates

[0002] The present invention generally relates to methods of treating cholestasis in a subject with a liver disease. More particularly, the present invention relates to methods of treating cholestasis in a subject, the method comprising administering to the patient an ASBTI at a dose of at least 10 mcg/kg/day.

Prior art of the present invention

[0003] Hypercholesterolemia and cholestatic liver diseases are liver diseases associated with impaired bile secretion (i.e., cholestasis) related to, and often secondary to, intracellular accumulation of bile acids/salts in hepatocytes. Hypercholesterolemia is characterized by elevated serum bile acids or bile salts. Clinicopathologically, cholestasis can be divided into two main categories: obstructive, often extrahepatic, cholestasis and non-obstructive, or intrahepatic, cholestasis. Non-obstructive intrahepatic cholestasis can be further divided into two main subgroups: primary intrahepatic cholestasis, which results from constitutively impaired bile secretion, and secondary intrahepatic cholestasis, which results from hepatocellular injury. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, which is predominantly an adult form with similar clinical features, and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3, which affect children.

[0004] Respiratory distress syndrome and neonatal pulmonary pneumonia are frequently associated with intrahepatic cholestasis of pregnancy. Active treatment and prevention are limited. Currently, effective treatments for hypercholeemia and cholestatic liver disease include surgery, liver transplantation, and, rarely, ursodiol. Effective and safe drugs for hypercholeemia and cholestatic liver disease are needed.

Brief summary of the present invention

[0005] Various non-limiting aspects and embodiments of the present invention are described below.

[0006] According to one aspect, the present invention provides a method of treating cholestatic liver disease in a subject, comprising administering to the subject an apical sodium-dependent bile acid transporter inhibitor (ASBTI). The ASBTI is administered in an amount of from about 10 mcg/kg/day to about 1400 mcg/kg/day.

[0007] According to certain embodiments, the ASBTI is an ASBTI that is

(maralixibat)

or a pharmaceutically acceptable alternative salt thereof,

(volixibate),

(odevixibat),

(elobixibat),

(GSK2330672)

or a pharmaceutically acceptable salt thereof. In various embodiments, the ASBTI is maralixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBTI is volixibat or a pharmaceutically acceptable salt thereof. In certain embodiments, the ASBTI is odevixibat or a pharmaceutically acceptable salt thereof. In various embodiments, the ASBTI is elobixibat or a pharmaceutically acceptable salt thereof. In certain embodiments, the ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the cholestatic liver disease is a pediatric cholestatic liver disease that results in subnormal growth or weight. In various embodiments, the cholestatic liver disease is selected from progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome (ALGS), primary sclerosing cholangitis (PSC), biliary atresia, intrahepatic cholestasis of pregnancy (ICP), or primary biliary cholangitis (PBC). In some embodiments, the cholestatic liver disease is biliary atresia. In various embodiments, the cholestatic liver disease is ICP.

[0009] In certain embodiments, the cholestatic liver disease is PFIC. In certain embodiments, the ASBTI is odevixibat. In certain embodiments, the ASBTI is maralixibat. In certain embodiments, the PFIC is selected from PFIC type 1, PFIC type 2, and PFIC type 3. In various embodiments, the PFIC is PFIC type 2. In some embodiments, the subject has a non-truncating mutation of the ABCB11 gene. In various embodiments, the subject is a pediatric subject. In certain embodiments, the ASBTI is administered once daily (QD).

[0010] In various embodiments, the ASBTI is administered twice daily (BID). In some embodiments, the ASBTI is administered in an amount of about 140 mcg/kg/day to about 1400 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 280 mcg/kg/day to about 1400 mcg/kg/day.

[0011] In certain embodiments, administration of an ASBTI results in a reduction in a symptom or a change in a disease-related laboratory value of a cholestatic liver disease that persists for at least one year. In various embodiments, the reduction in a symptom or a change in a disease-related laboratory value comprises a reduction in sBA concentration, an increase in serum 7α-hydroxy-4-cholesten-3-one (7αC4) concentration, an increase in the ratio of serum 7αC4 concentration to serum bile acid (sBA) concentration (7αC4:sBA), a reduction in pruritus, an increase in a quality of life score, an increase in a fatigue-related quality of life score, an increase in height, or a combination thereof. In some embodiments, the reduction in a symptom or a change in a disease-related laboratory value is determined relative to a baseline. In some embodiments, the reduction in a symptom or a change in a disease-related laboratory value comprises an increase in height. According to various embodiments, an increase in the height of a pediatric subject is measured as an increase in a height Z-score or a weight Z-score.

[0012] In certain embodiments, administration of an ASBTI results in an increase in the serum concentration of 7αC4. In some embodiments, the serum concentration of 7αC4 increases from about 1.5-fold to about 40-fold relative to baseline. In various embodiments, the serum concentration of 7αC4 is increased by at least 100% relative to baseline. In some embodiments, administration of an ASBTI results in an increase in the ratio of serum concentration of 7αC4 to concentration of sBA (7αC4:sBA). In certain embodiments, 7αC4:sBA increases from about 2-fold to about 5,000-fold relative to baseline.

[0013] According to various embodiments, the method further comprises administering a second dose of the ASBTI, wherein the second dose is greater than the first dose, if, following administration of the first dose of the ASBTI, 7αC4:sBA is not maintained at about >2 times the baseline. According to some embodiments, the method further comprises administering a second dose of the ASBTI, wherein the second dose is greater than the first dose, if 7αC4:sBA initially increases by at least more than 2 times the baseline ratio; and then begins to decline back toward the baseline ratio.

[0014] In various embodiments, administration of the ASBTI results in a decrease in the sBA concentration by at least about 70% relative to baseline. In certain embodiments, administration of the ASBTI results in a decrease in the severity of pruritus. In various embodiments, a decrease in the severity of pruritus is measured as a decrease of at least 1.0 point in the Observer Reported Outcome of Pruritus (ITCHRO(OBS)). In some embodiments, administration of the ASBTI results in an ITCHRO(OBS) score ≤ 1. In various embodiments, administration of the ASBTI results in an increase in a quality of life score or a fatigue-related quality of life score. In certain embodiments, the quality of life score is a fatigue-related health-related quality of life (HRQoL) score. In various embodiments, the quality of life score is a Pediatric Quality of Life Questionnaire (PedsQL) score, and the PedsQL score increases by at least 10% relative to baseline.

[0015] In some embodiments, the serum bilirubin concentration is at baseline prior to administration about 4 months after the first administration of the ASBTI. In some embodiments, the serum alanine aminotransferase (ALT) concentration is at baseline prior to administration about 4 months after the first administration of the ASBTI. In certain embodiments, the serum aspartate aminotransferase (AST) concentration and the serum bilirubin concentration are within normal limits about 4 months after the first administration of the ASBTI. In various embodiments, administration of the ASBTI results in a decrease in serum ALT concentration by at least about 10% relative to baseline.

[0016] In some embodiments, the cholestatic liver disease is ALGS. In various embodiments, the subject is a pediatric subject.

[0017] In certain embodiments, the ASBTI is administered once per day (QD). In various embodiments, the ASBTI is administered twice per day (BID). In some embodiments, the ASBTI is administered in an amount of about 140 mcg/kg/day to about 1400 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 280 mcg/kg/day to about 1400 mcg/kg/day.

[0018] In certain embodiments, administration of an ASBTI results in a reduction in a symptom or a change in a disease-related laboratory value of cholestatic liver disease that persists for at least 6 months. In various embodiments, the reduction in a symptom or a change in a disease-related laboratory value includes a decrease in sBA concentration, an increase in serum 7αC4 concentration, a decrease in pruritus, an increase in a quality of life score, an increase in a quality of life score associated with fatigue; a decrease in a xanthoma score; an increase in height, or a combination thereof. In some embodiments, the reduction in a symptom or a change in a disease-related laboratory value is determined relative to a baseline. In various embodiments, the reduction in a symptom or a change in a disease-related laboratory value includes an increase in height. In some embodiments, an increase in height in a pediatric subject is measured as an increase in a height Z-score or a weight Z-score. In certain embodiments, the reduction in a symptom or change in a disease-related laboratory value is maintained for at least 2 years.

[0019] In various embodiments, administration of an ASBTI results in a reduction in the severity of pruritus. In some embodiments, the subject's ITCHRO(OBS) score is reduced by at least 40% relative to baseline. In certain embodiments, the subject's CSS score is reduced by at least 50% relative to baseline. In various embodiments, the subject has an ITCHRO(OBS) score of ≤1 on at least 50% of days after 6 months. In certain embodiments, administration of an ASBTI results in a persistent and progressive reduction in the severity and frequency of pruritus over time.

[0020] In some embodiments, administration of an ASBTI results in a decrease in sBA concentration by at least 30% by 18 weeks. In various embodiments, administration of an ASBTI results in a decrease in sBA concentration by at least 50%. In certain embodiments, administration of an ASBTI coincides with a positive correlation between a decrease in sBA concentration and a decrease in the severity of pruritus. In some embodiments, administration results in a decrease in the xanthoma score in the subject by at least 25%.

[0021] In various embodiments, administration of the ASBTI results in an increase in a quality of life score. In some embodiments, the quality of life score is a health-related quality of life (HRQoL) score. In certain embodiments, the quality of life score is a Pediatric Quality of Life Questionnaire (PedsQL) score, wherein the PedsQL score increases by at least 10% relative to baseline. In some embodiments, administration of the ASBTI results in a decrease in serum cholesterol concentration by at least 15% by 18 weeks. In some embodiments, administration of the ASBTI results in an increase in serum 7αC4 concentration by at least 50% by about 18 weeks.

[0022] In certain embodiments, the ASBTI is administered for up to 3 years. In various embodiments, the ASBTI is administered for up to 4 years.

[0023] In various embodiments, the cholestatic liver disease is PSC and the ASBTI is volixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is an adult. In some embodiments, the ASBTI is administered once daily (QD). In various embodiments, the ASBTI is administered twice daily (BID). In various embodiments, the ASBTI is administered in an amount of from about 0.5 mg/day to about 100 mg/day.

[0024] In some embodiments, administration of an ASBTI results in a reduction in a symptom or a change in a disease-related laboratory value of cholestatic liver disease that is maintained for at least four weeks. In various embodiments, the reduction in a symptom or a change in a disease-related laboratory value comprises a decrease in sBA concentration, an increase in serum 7αC4 concentration, a decrease in serum autotaxin concentration, a decrease in pruritus, an increase in a quality of life score, an increase in a fatigue-related quality of life score, or a combination thereof. In certain embodiments, the reduction in a symptom or a change in a disease-related laboratory value is determined relative to a baseline.

[0025] In some embodiments, the degree of symptom reduction or change in disease-related laboratory values is positively correlated with the subject's baseline ITCHRO score. In certain embodiments, the degree of symptom reduction or change in disease-related laboratory values is greater if the subject has a baseline ITCHRO score of at least four than if the subject has a baseline ITCHRO score of less than 4.

[0026] In various embodiments, administration of an ASBTI results in a reduction in the severity of pruritus. In various embodiments, the subject's ITCHRO score is reduced by at least 40% from baseline by 14 weeks. In some embodiments, the subject's ITCHRO score is reduced by at least 60% from a baseline ITCHRO score of 4 or greater.

[0027] In certain embodiments, administration of an ASBTI results in a decrease in sBA concentration by at least 30% relative to baseline. In some embodiments, the sBA concentration is decreased by at least 45% relative to baseline if the subject has a baseline ITCHRO of at least 4. In various embodiments, administration of an ASBTI results in a decrease in serum total cholesterol concentration by at least 10 mg/dL. In some embodiments, the decrease in serum total cholesterol concentration is at least 12.5 mg/dL if the subject has a baseline ITCHRO of at least 4.

[0028] In certain embodiments, administration of the ASBTI results in a decrease in serum LDL cholesterol concentration by at least 5%. In various embodiments, administration of the ASBTI results in a decrease in serum LDL cholesterol concentration by at least 10 mg/dL. In some embodiments, administration of the ASBTI results in an increase in serum 7αC4 concentration by at least 30% relative to baseline.

[0029] In certain embodiments, administration of an ASBTI results in a decrease in serum autotaxin concentration by at least 50% if the subject has a baseline ITCHRO score of at least 4. In various embodiments, administration of an ASBTI results in a decrease in serum autotaxin concentration by at least 10% by week 6 and by 20% by week 14. In various embodiments, administration of an ASBTI does not result in a significant change from baseline in serum conjugated bilirubin concentration if the subject has a baseline ITCHRO score of at least 4. In various embodiments, administration of an ASBTI does not result in a significant change from baseline in serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or some combination thereof.

[0030] In some embodiments, by day 28 of administration, the subject's fecal bile acid (fBA) excretion increases by at least 250 μmol. In certain embodiments, by day 7 of administration, the subject's fBA excretion increases by at least 1000 μmol. In some embodiments, by day 7 of ASBTI administration, the subject's fBA excretion increases by at least 1.5-fold relative to baseline. In various embodiments, administration of the ASBTI results in at least a 4-fold increase in fBA excretion relative to baseline. In some embodiments, administration of the ASBTI results in a dose-dependent increase in fBA excretion.

[0031] These and other aspects of the present invention will become apparent to those skilled in the art upon reading the following detailed description of the present invention, including the appended claims.

Brief description of graphic materials

[0032] Fig. 1 is a schematic diagram summarizing the physiological effects of maralixibat administration in a patient. CYP7A1, cholesterol 7α-hydroxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor.

[0033] Figure 2 is a flow chart providing an overview of the dosing schedule used in the Phase 2, open-label INDIGO clinical trial of maralixibat in children with PFIC. The clinical trial examined long-term exposure to maralixibat.

[0034] Figures 3A-3F show quantitative summary results of the response rates measured for the six responders who participated in the INDIGO clinical study. The six responders were a 3-year-old girl (Figure 3A), a 10-year-old boy (Figure 3B), a 6-year-old girl and the 10-year-old boy's sister (Figure 3C), a 4-year-old girl (Figure 3D), a 3-year-old boy (Figure 3E), and a 1-year-old girl (Figure 3F). Each of Figures 3A-3F shows three scatter plots displaying sBA concentrations, Pruritus Severity Score, and Pediatric Disease Quality of Life Questionnaire (PEDSQL) scores by study week, respectively. Pruritus Severity Score was measured according to the Clinical Scratch Scale (CSS) and the Itch Rating Outcome Measure (ITCHRO). Each of Figures 3A-3F also present the summary results of changes observed in ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels, bilirubin levels, and C4 levels for each responder.

[0035] Fig. 4 is a correlation plot showing the change in height Z-score from baseline over time for responders and non-responders in the INDIGO clinical trial. The decrease in mean height Z-score at week 60 is due to one patient not having measurements at that time point.

[0036] Figures 5A and 5B are correlation plots depicting serum bile acid (sBA) concentrations over time for patients who participated in the INDIGO clinical trial. Figure 5A shows plots of sBA concentrations over time for patients with non-truncating mutations of the bile salt efflux pump (BSEP, which is encoded by the ABCB11 gene). Figure 5B shows plots of sBA concentrations over time for patients with truncating mutations of BSEP. Figures 5A-5B show that sBA responses differed by BSEP mutation status. Black filled circles indicate discontinuation. White filled circles indicate initiation of BID dosing (280 μg/kg BID). In Figures 5A and 5B, lines corresponding to non-responders are marked with an asterisk.

[0037] Figure 6 is a correlation plot showing the weekly mean observer-reported pruritus outcome scores (ITCHRO(OBS)) for patients in the INDIGO clinical trial who have non-truncating BSEP mutations. Figure 6 shows that the ITCHRO(OBS) response was maintained over many years and that >50% (10/19) of patients demonstrated a decrease of ≥1.0 point in the ITCHRO(OBS) score. Black filled circles indicate discontinuation. White filled circles indicate the start of BID dosing (280 mcg/kg BID). The ITCHRO(OBS) score ranges from 0 to 4. In Figure 6, the lines representing non-responders are marked with an asterisk.

[0038] Figure 7 is a correlation plot of mean serum 7α-hydroxy-4-choesten-3-one (7αC4 or C4) concentrations over time for patients in the INDIGO clinical trial with non-truncating BSEP mutations. Figure 7 shows that responders with non-truncating BSEP mutations had significant increases in 7αC4 concentrations. Black filled circles indicate discontinuation. White filled circles indicate initiation of BID dosing (280 mcg/kg BID). The ITCHRO(OBS) scale ranges from 0 to 4. In Figure 7, lines representing non-responders are marked with an asterisk.

[0039] Figure 8 is a correlation plot showing the ratio of 7αC4 concentration to sBA concentration (7αC4:sBA) over time for patients in the INDIGO clinical trial with non-truncating BSEP mutations. Figure 8 shows that responders with non-truncating BSEP mutations had significantly different 7αC4:sBA ratios than non-responders. Two responders with non-truncating BSEP mutations showed an increase in 7αC4:sBA ratio after dose escalation. Black filled circles indicate discontinuation. White filled circles indicate the start of BID dosing (280 μg/kg BID). The ITCHRO(OBS) scale ranges from 0 to 4. In Figure 8, the lines corresponding to non-responders are marked with an asterisk.

[0040] Figure 9 is a histogram showing the mean change from baseline in fBA to days 6 and 7 for the indicated doses of maralixibat, volixibat, and placebo for the phase 1, blinded, placebo-controlled, dose-finding clinical trial (NCT02475317). BID, twice daily; QD, once daily; SE, standard error.

[0041] Figure 10 is a histogram showing the mean change in serum 7αC4 concentration from baseline to day 7 for the indicated doses of maralixibat, volixibat, and placebo. BID, twice daily; fBA, faecal bile acids; QD, once daily; SE, standard error.

[0042] Fig. 11 is a histogram showing the mean weekly ITCHRO total scores in the overall population of participants in the Phase 2a, 14-week, single-arm, open-label, proof-of-concept study of maralixibat (CAMEO clinical study) with any pruritus at baseline and participants with daily ITCHRO scores ≥4 at baseline.

[0043] Figure 12 shows histograms of sBA concentration (left panel) and 7αC4 concentration (right panel) in the overall population participating in the CAMEO clinical study and in participants with ITCHRO daily scores ≥4 at baseline.

[0044] Figure 13 shows histograms of serum autotaxin concentrations (left panel) and serum low-density lipoprotein cholesterol (LDL-C) concentrations (right panel) in the overall population participating in the CAMEO clinical trial and in participants with ITCHRO daily scores ≥4 at baseline.

[0045] Figure 14 shows a histogram of the percent change from baseline to week 14 or early discontinuation in efficacy measures, including ITCHRO score (day 1-10 score), sBA concentration, and serum autotaxin concentration in six participants in the CAMEO clinical trial with ITCHRO day scores ≥4 at baseline.

[0046] Fig. 15 is a flow chart summarizing the clinical study design for the double-blind, randomized, placebo-controlled, long-term open-label treatment withdrawal study with maralixibat 400 mcg/kg QD (the ICONIC clinical study).

[0047] Fig. 16 is a diagram summarizing the distribution of participants in the ICONIC clinical trial.

[0048] Figures 17A and 17B show significant improvements in sBA compared to baseline and placebo in participants in the ICONIC clinical trial. Figure 17A shows a graph of the mean change in sBA concentration from baseline in all participants through week 48. Figure 17B shows a histogram showing the mean change in sBA from weeks 8 to 22 in sBA responders during randomized withdrawal.

[0049] Figure 18 shows a graph of mean sBA concentrations for participants in the ICONIC clinical study during the core study (first 48 weeks) and during the extension (post-48 week period). MRX = maralixibat; PLA = placebo.

[0050] Fig. 19 is a histogram showing the mean change from baseline (BL) in sBA observed in the ICONIC clinical study.

[0051] Figures 20A and 20B show the improvement in ITCHRO(OBS) scores maintained during randomized maralixibat withdrawal in participants in the ICONIC clinical trial. Figure 20A shows the mean change from baseline in ITCHRO(OBS) score for participants over time. Figure 20B shows a plot of ITCHRO(OBS) score for participants during the placebo-controlled withdrawal period.

[0052] Figures 21A and 21B show improvements from baseline in Clinical Scratch Score (CSS) scores throughout the ICONIC clinical study. Figure 21A shows the proportions of total patients who reported CSS scores at baseline, week 18, and week 48. Figure 21B shows the proportions of total patients who received maralixibat or placebo reporting CSS scores during the placebo-controlled washout period at week 22.

[0053] Fig. 22 shows the change from baseline (BL) in CSS for ICONIC clinical trial participants at Week 48 and Week 191.

[0054] FIGS. 23A-23D are graphs of average weekly ITCHRO(OBS) score over time for participants in the ICONIC clinical study during the core study and during the extension study. FIG. 23A is a correlation plot showing average ITCHRO(OBS) score over time. FIG. 23B shows that the reduction in pruritus was maintained over an extended period of time. Each line represents the ITCHRO(OBS) scores for an individual patient. FIGS. 23C and 23D show that the reduction in pruritus was maintained by maralixibat but not by the crossover to the placebo washout period (denoted by the rectangular area on the graph). Each line represents the ITCHRO(OBS) scores for an individual patient. MRX = maralixibat; PLA = placebo. N = number of participants measured at the indicated time point.

[0055] Figure 24 shows the change from baseline (BL) in ITCHRO(OBS) score at 48 weeks and at 193 weeks for participants in the ICONIC clinical trial.

[0056] Fig. 25 is a histogram showing the proportion of study days with ITCHRO(OBS) ≤1 among all participants (%) in the ICONIC clinical study during placebo administration and during maralixibat administration.

[0057] Fig. 26 shows a histogram of HRQoL scores over time for patients participating in the ICONIC clinical trial. HRQoL scores were measured as PEDSQL scores.

[0058] Fig. 27 is a histogram showing the change from baseline (BL) in PEDSQL fatigue scale score (0-100 scale) at Week 48 and Week 191 for participants in the ICONIC clinical study, n = number of participants represented at the indicated time point.

[0059] Fig. 28 shows a graph of the Clinical Xanthoma Score scores over time for patients participating in the ICONIC clinical trial.

[0060] Fig. 29 is a histogram showing the change from baseline (BL) in Clinical Xanthoma Scale scores for participants in the ICONIC clinical trial at Week 48 and Week 191.

[0061] Fig. 30 is a correlation graph showing serum concentrations of liver function indicators over time for participants in the ICONIC clinical trial. GGT, gamma-glutamyl transpeptidase.

[0062] Fig. 31 shows a graph of the percent change in sBA from baseline versus the change in weekly average morning ITCHRO(OBS) from baseline for participants in the ICONIC clinical trial at Week 48.

[0063] FIGS. 32A-32H show trellis plots for each participant (identified by the subject number above each plot) in the ICONIC clinical study through Week 48. FIGS. 32A-32H show trellis plots of sBA concentration (blue; left axis; μmol/L) and average weekly ITCHRO(OBS) (red; right axis) over time (bottom axis) for each participant in the ICONIC clinical study. FIGS. 32A and 32D show trellis plots for patients in the MRX-MRX-MRX study arm, which includes only those patients who were administered maralixibat before, during, and after the placebo-controlled washout period in the ICONIC clinical study. 32E and 32H show trellis plots for patients in the MRX-Placebo-MRX study arm, which includes only those patients who were administered maralixibat before, placebo during, and maralixibat again after the placebo-controlled washout period. Patient 090004 did not have post-baseline assessments, so the baseline data point is not plotted.

[0064] Figure 33 shows a correlation plot of the mean change in height Z-score from baseline over time for all participants in the ICONIC clinical trial. The number of patients (N) measured at each data point is indicated below the abscissa. BL = baseline.

[0065] Fig. 34 shows a correlation plot of the mean change from baseline in growth Z-score over time for ICONIC clinical trial participants who agreed to the long-term extension of the ICONIC clinical trial and were enrolled in the study for up to approximately four years (n=15). The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

[0066] Figure 35 shows a correlation plot of the mean change from baseline in mass Z-score over time for all participants in the ICONIC clinical trial (n=31). The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

[0067] Fig. 36 shows a correlation plot of the mean change from baseline in height Z-score over time for ICONIC clinical trial participants who agreed to the long-term extension of the ICONIC clinical trial and were enrolled in the study for up to approximately four years (n=15). The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

Detailed disclosure of the present invention

[0068] Detailed embodiments of the present invention are disclosed herein; however, it should be understood that the disclosed embodiments are merely illustrative of the present invention, which may be embodied in various forms. Furthermore, each of the examples given in connection with various embodiments of the present invention is intended to be illustrative and not limiting. Accordingly, the specific structural and functional details disclosed herein should not be interpreted as limiting, but merely as a representative basis for teaching those skilled in the art various ways to use the present invention.

[0069] Bile acids/salts play a critical role in the activation of digestive enzymes and the solubility of fats and fat-soluble vitamins and are involved in diseases of the liver, biliary tract, and intestine. Bile acids are synthesized in the liver by a multistep, multiorganellar pathway. Hydroxyl groups are added to specific sites on the steroid structure, the double bond of the cholesterol B-ring is reduced, and the hydrocarbon chain is shortened by three carbon atoms to form a carboxyl group at the end of the chain. The most common bile acids are cholic acid and chenodeoxycholic acid (the "primary bile acids"). Before leaving the hepatocytes to form bile, bile acids are conjugated with either glycine (to produce glycocholic acid or glycochenodeoxycholic acid) or taurine (to produce taurocholic acid or taurochenodeoxycholic acid). Conjugated bile acids are called bile salts, and their amphipathic nature makes them more effective detergents than bile acids. Bile salts, not bile acids, are found in bile.

[0070] Bile salts are secreted by hepatocytes into the canaliculi to form bile. The canaliculi drain into the right and left hepatic ducts, and bile flows into the gallbladder. Bile is secreted from the gallbladder and enters the duodenum, where it aids in the metabolism and breakdown of fats. Bile salts are reabsorbed in the terminal ileum and transported back to the liver via the portal vein. Bile salts often undergo multiple enterohepatic circulations before being excreted in the feces. A small percentage of bile salts may be reabsorbed in the proximal intestine by either passive or carrier-mediated transport processes. The majority of bile salts are regenerated in the distal ileum by a sodium-dependent, apically located bile acid transporter called the apical sodium-dependent bile acid transporter (ASBT). On the basolateral surface of the enterocyte, a truncated version of the ASBT is involved in the vectorial transport of bile acids/salts into the portal circulation. Completion of the enterohepatic circulation occurs on the basolateral surface of the hepatocyte through a transport process that is primarily mediated by the sodium-dependent bile acid transporter. Intestinal bile acid transport plays a key role in the enterohepatic circulation of bile salts. Molecular analysis of this process has recently led to important advances in understanding the biology, physiology, and pathophysiology of intestinal bile acid transport.

[0071] In the intestinal lumen, bile acid concentrations vary, with the majority of reuptake occurring in the distal intestine. Disclosed herein are certain compositions and methods that control the concentration of bile acids in the intestinal lumen, thereby controlling hepatocellular injury caused by bile acid accumulation in the liver.

Classes of cholestasis and cholestatic liver disease

[0072] As used herein, the term "cholestasis" means a disease or symptoms involving an impairment of bile formation and/or bile flow. As used herein, the term "cholestatic liver disease" means a liver disease associated with cholestasis. Cholestatic liver diseases are often accompanied by jaundice, fatigue, and pruritus. Biomarkers of cholestatic liver disease include elevated serum bile acid concentrations, elevated serum alkaline phosphatase (AP), elevated gamma-glutamyl transpeptidase, elevated conjugated hyperbilirubinemia, and elevated serum cholesterol.

[0073] Cholestatic liver disease can be divided clinically and pathologically into two main categories: obstructive, often extrahepatic, cholestasis and non-obstructive, or intrahepatic, cholestasis. In the former case, cholestasis occurs when the outflow of bile is mechanically blocked, for example by gallstones or a tumor or as in extrahepatic biliary atresia.

[0074] The final group with non-obstructive intrahepatic cholestasis is further divided into two major subgroups. In the first subgroup, cholestasis occurs when the processes of bile secretion and modification or synthesis of bile components are involved in hepatocellular injury to such an extent that non-specific impairment of many functions, including those that contribute to bile formation, can be expected. In the second subgroup, no presumed cause of hepatocellular injury can be determined. Cholestasis in such patients presumably occurs when one of the steps in bile secretion or modification or synthesis of bile components is constitutively impaired. Such cholestasis is considered primary.

[0075] Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or intestinal mucosal regeneration and/or enhancing intestinal adaptive processes in individuals with hypercholesterolemia and/or cholestatic liver disease. In some such embodiments, the methods comprise increasing the concentration of bile acid and/or the concentration of GLP-2 in the intestinal lumen.

[0076] Elevated bile acids and elevated AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma-GT (gamma-glutamyl transpeptidase) and 5'-nucleotidase are biochemical hallmarks of cholestasis and cholestatic liver disease. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or intestinal mucosal regeneration and/or enhancing intestinal adaptive processes in individuals with hypercholeemia and elevated AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma-GT (gamma-glutamyl transpeptidase or GGT) and/or 5'-nucleotidase. In some such embodiments, the methods comprise increasing the concentration of bile acid in the intestinal lumen. In addition, the present document provides methods and compositions for reducing hypercholesterolemia and elevated AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma-GT (gamma-glutamyl transpeptidase) and 5'-nucleotidase levels, involving a reduction in the total bile acid load in the serum by eliminating bile acid in the feces.

[0077] Pruritus is often associated with hypercholesterolemia and cholestatic liver disease in pediatric patients. It has been suggested that pruritus is a result of the action of bile salts on peripheral pain afferent nerves. The degree of pruritus varies among individuals (i.e., some individuals are more sensitive to elevated bile acids/salts).

[0078] Administration of serum bile acid lowering agents has been shown to reduce pruritus in some individuals. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or intestinal mucosal regeneration and/or enhancing intestinal adaptive processes in individuals with pruritus. In some such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. Also provided herein are methods and compositions for treating pruritus comprising reducing the total serum bile acid load by excreting bile acids in feces.

[0079] Another symptom of hypercholesterolemia and cholestatic liver disease is an increase in the concentration of conjugated bilirubin in the blood serum. Elevated concentrations of conjugated bilirubin in the blood serum cause jaundice and dark urine. The magnitude of the increase is not diagnostically important, since no relationship has been established between the levels of conjugated bilirubin in the blood serum and the severity of hypercholesterolemia and cholestatic liver disease. The concentration of conjugated bilirubin rarely exceeds 30 mg/dL. Accordingly, methods and compositions are provided herein for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa and/or enhancing intestinal adaptive processes in individuals with elevated concentrations of conjugated bilirubin in the blood serum. According to some of such embodiments, the methods comprise increasing the concentration of bile acid in the intestinal lumen. In addition, the present document provides methods and compositions for treating elevated serum conjugated bilirubin concentrations that include reducing the total serum bile acid load by excreting bile acids in feces.

[0080] Elevated serum unconjugated bilirubin is also considered diagnostic of hypercholesterolemia and cholestatic liver disease. Portions of serum bilirubin are covalently bound to albumin (delta-bilirubin or biliprotein). This fraction can account for a large proportion of total bilirubin in patients with cholestatic jaundice. The presence of large amounts of delta-bilirubin indicates prolonged cholestasis. Delta-bilirubin in cord blood or neonatal blood indicates cholestasis/cholestatic liver disease that precedes birth. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration of intestinal mucosa and/or enhancing intestinal adaptive processes in individuals with elevated serum concentrations of unconjugated bilirubin or delta-bilirubin. According to some of such embodiments, the methods involve increasing the concentration of bile acids in the intestinal lumen. In addition, the present document provides methods and compositions for treating elevated serum unconjugated bilirubin and delta-bilirubin concentrations, which involve reducing the total bile acid load in the serum by excreting bile acids in feces.

[0081] Cholestasis and cholestatic liver disease result in hypercholesterolemia. During metabolic cholestasis, hepatocytes retain bile salts. Bile salts are released from hepatocytes into the serum, which leads to an increase in the concentration of bile salts in the peripheral circulation. In addition, the uptake of bile salts entering the liver by the portal vein blood is inefficient, which leads to leakage of bile salts into the peripheral circulation. Accordingly, methods and compositions for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa and/or enhancing intestinal adaptive processes in individuals with hypercholesterolemia are provided herein. According to some of such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. In addition, methods and compositions for treating hypercholesterolemia comprising reducing the total bile acid load in the serum by excreting bile acids in feces are provided herein.

[0082] Hyperlipidemia is characteristic of some, but not all, cholestatic diseases. Serum cholesterol is elevated in cholestasis due to a decrease in circulating bile salts, which promote the metabolism and degradation of cholesterol. Cholesterol retention is associated with increased membrane cholesterol and decreased membrane fluidity and function. In addition, since bile salts are products of cholesterol metabolism, decreased cholesterol metabolism results in decreased bile acid/salt synthesis. Serum cholesterol levels observed in children with cholestasis range from 1000 mg/dL to 4000 mg/dL. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or intestinal mucosal regeneration and/or enhancing intestinal adaptive processes in individuals with hyperlipidemia. In some such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. In addition, the present document provides methods and compositions for treating hyperlipidemia that involve reducing the total serum bile acid load by excreting bile acids in feces.

[0083] In individuals with hypercholesterolemia and cholestatic liver diseases, xanthomas develop as a result of the deposition of excess circulating cholesterol in the dermis. The development of xanthomas is more characteristic of obstructive cholestasis than of hepatocellular cholestasis. Flat xanthomas first occur around the eyes, then in the creases of the palms and soles, and then on the neck. Tuberous xanthomas are associated with chronic and long-term cholestasis. Accordingly, methods and compositions are provided herein for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa and/or enhancing intestinal adaptive processes in individuals with xanthomas. According to some of such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. In addition, the present document provides methods and compositions for the treatment of xanthomas that involve reducing the total bile acid load in the serum by excreting bile acids in the feces.

[0084] In children with chronic cholestasis, failure to thrive is a major consequence of hypercholesterolemia and cholestatic liver disease. Failure to thrive results from decreased delivery of bile salts to the intestine, which contributes to inefficient fat digestion and absorption, as well as decreased vitamin absorption (vitamins E, D, K, and A are not absorbed in cholestasis). In addition, fat delivery to the colon may result in colonic secretion and diarrhea. Treatment of failure to thrive involves dietary replacement and supplementation with long-chain triglycerides, medium-chain triglycerides, and vitamins. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and does not affect fat absorption. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or intestinal mucosal regeneration and/or enhancing intestinal adaptive processes in individuals (e.g., children) with impaired normal development. According to some of such embodiments, the methods comprise increasing the concentration of bile acids in the intestinal lumen. Also provided herein are methods and compositions for treating developmental delay comprising reducing the total serum bile acid load by excreting bile acids in feces.

Primary biliary cirrhosis (PBC)

[0085] Primary biliary cirrhosis is an autoimmune liver disease characterized by destruction of the bile ducts. Damage to the bile ducts results in accumulation of bile in the liver (i.e., cholestasis). Retention of bile in the liver damages liver tissue and can lead to scarring, fibrosis, and cirrhosis. PBC typically presents in adulthood (eg, 40 years of age or older). Individuals with PBC often complain of fatigue, pruritus, and/or jaundice. PBC is diagnosed if an individual has elevated AR concentrations for at least 6 months, elevated gamma-GT, serum antimitochondrial antibodies (AMA) (>1:40), and bile duct lesions. Serum ALT, serum AST, and conjugated bilirubin may also be elevated but are not considered diagnostic. Cholestasis associated with RVS has been treated or improved by administration of ursodeoxycholic acid (UDCA or ursodiol). Corticosteroids (eg, prednisone and budesonide) and immunosuppressants (eg, azathioprine, cyclosporine A, methotrexate, chlorambucil, and mycophenolate) are used to treat cholestasis associated with RVS. Sulindac, bezafibrate, tamoxifen, and lamivudine have also been shown to treat or improve cholestasis associated with RVS.

Progressive familial intrahepatic cholestasis (PFIC)

PFIC is a rare genetic disorder that causes progressive liver disease, usually leading to liver failure. In people with PFIC, liver cells are less able to secrete bile. The resulting buildup of bile causes liver disease in affected individuals. Signs and symptoms of PFIC typically begin in infancy. Patients experience severe itching, jaundice, failure to grow at the expected rate (failure to thrive), and increasing failure of the liver to function (liver failure). The disease is estimated to affect one in every 50,000 to 100,000 births in the United States and Europe. Six types of PFIC have been genetically identified, and all are characterized by similar bile flow problems and progressive liver disease.

PFIC 1

[0086] PFIC 1 (also known as Byler's disease or FIC1 deficiency) is associated with mutations in the ATP8 B1 gene (also referred to as FIC1). This gene, which encodes a P-type ATPase, is located on human chromosome 18 and also contains a mutation in a milder phenotype, benign recurrent intrahepatic cholestasis type 1 (BRIO) and familial Greenland cholestasis. The FIC1 protein is located on the canalicular membrane of the hepatocyte, but in the liver it is primarily expressed in cholangiocytes. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining phosphatidylserine and phosphatidylethanolamine enrichment at the inner leaflet of the plasma membrane compared to the outer leaflet. The asymmetric distribution of lipids in the membrane bilayer plays a protective role against high concentrations of bile salts in the lumen of the channel. Impaired protein function may indirectly impair bile acid secretion into bile. Abnormal secretion of bile acids/salts leads to bile acid overload of hepatocytes.

[0087] PFIC 1 typically presents in infants (eg, 6-18 months of age). Infants may present with pruritus, jaundice, abdominal distension, diarrhea, malnutrition, and poor growth. Biochemically, individuals with PFIC 1 are characterized by elevated serum transaminases, elevated bilirubin, elevated serum bile acids, and low gamma-GT. The individual may also have liver fibrosis. Individuals with PFIC 1 typically do not have bile duct proliferation. Most individuals with PFIC 1 develop end-stage liver disease by age 10 years. No medications have been shown to be effective for the long-term treatment of PFIC 1. Medium-chain triglycerides and fat-soluble vitamins are often given to children to reduce extrahepatic symptoms (eg, malnutrition and poor growth). Ursodiol has not been shown to be effective in individuals with PFIC 1.

PFIC 2

[0088] PFIC 2 (also known as Byler syndrome or BSEP deficiency) is associated with mutations in the ABCB11 gene (also referred to as BSEP). The ABCB11 gene encodes the ATP-dependent bile salt efflux pump (BSEP) of the human liver and is located on human chromosome 2. The BSEP protein, expressed on the canalicular membrane of hepatocytes, is the major exporter of primary bile acids/salts in extreme concentration gradients. Mutations in this protein are responsible for the decreased secretion of bile salts described in affected patients, resulting in decreased bile flow and accumulation of bile salts within the hepatocyte with ongoing severe hepatocellular injury.

[0089] PFIC 2 typically presents in infants (eg, 6-18 months of age). Infants may present with pruritus. Biochemically, individuals with PFIC 2 are characterized by elevated serum transaminases, elevated bilirubin, elevated serum bile acids, and low gamma-GT. The individual may also have portal inflammation and giant cell hepatitis. In addition, individuals frequently develop hepatocellular carcinoma. No medications have been shown to be effective for the long-term treatment of PFIC 2. Medium-chain triglycerides and fat-soluble vitamins are often given to children to reduce extrahepatic symptoms (eg, malnutrition and growth retardation). The PFIC 2 patient population represents approximately 60% of the overall PFIC population.

PFIC 3

[0090] PFIC 3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also referred to as MDR3) located on chromosome 7. Multidrug-resistant class III P-glycoprotein (P-gp) (MDR3) is a phospholipid translocator involved in the excretion of biliary phospholipid (phosphatidylcholine) across the hepatocyte canalicular membrane. PFIC 3 results from bile toxicity in which bile salts of detergents are not inactivated by phospholipids, resulting in damage to the bile ducts and biliary epithelium.

[0091] PFIC 3 is also present in early childhood. Unlike PFIC 1 and PFIC 2, individuals have elevated gamma-GT. Individuals also have portal inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. Individuals may also develop intrahepatic cholelithiasis. Ursodiol has been effective in treating or alleviating PFIC 3.

Benign recurrent intrahepatic cholestasis (BRIC)

BRIC 1

[0092] BRIC 1 is caused by a genetic defect in the FIC1 protein in the canalicular membrane of hepatocytes. BRIC1 is typically associated with normal serum cholesterol and γ-glutamyl transpeptidase levels, but elevated serum bile salts. Residual FIC1 expression and function are associated with BRIC1. Despite recurrent attacks of cholestasis or cholestatic liver disease, most patients do not progress to chronic liver disease. During attacks, patients experience severe jaundice, pruritus, steatorrhea, and weight loss. Some patients also have renal calculi, pancreatitis, and diabetes mellitus.

BRIC 2

[0093] BRIC 2 is caused by mutations in ABCB11 that result in impaired expression and/or function of BSEP in the hepatocyte tubular membrane.

BRIC 3

[0094] BRIC 3 is associated with defective expression and/or function of MDR3 in the hepatocyte canalicular membrane. Patients with MDR3 deficiency typically have elevated serum gamma-glutamyl transpeptidase levels with normal or slightly elevated bile acid levels.

Dubin-Johnson syndrome (DJS)

[0095] DJS is characterized by conjugated hyperbilirubinemia due to inherited dysfunction of MRP2. Liver function is preserved in affected patients. Several different mutations have been associated with this condition, resulting in either a complete absence of immunohistochemically detectable MRP2 in affected patients or defects in protein maturation and sorting.

Acquired cholestatic disease

Primary biliary cirrhosis (PBC)

[0096] RVS is a chronic inflammatory liver disease that slowly progresses to end-stage liver failure in most affected patients. In RVS, the inflammatory process primarily affects the small bile ducts.

Primary sclerosing cholangitis in pediatric patients (PSC)

[0097] PSC is a chronic inflammatory liver disease that slowly progresses to end-stage liver failure in most affected patients. PSC is characterized by inflammation, fibrosis, and obstruction of large and medium-sized intra- and extrahepatic ducts.

[0098] PSC is characterized by progressive cholestasis. Cholestasis can often lead to severe itching, which significantly impairs quality of life.

Intrahepatic cholestasis of pregnancy (ICP)

[0099] ICP is characterized by the occurrence of transient cholestasis or cholestatic liver disease in pregnant women, typically occurring in the third trimester of pregnancy when circulating estrogen levels are high. ICP is associated with pruritus and biochemical cholestasis or cholestatic liver disease of varying severity and is a risk factor for prematurity and intrauterine fetal death. A genetic predisposition has been suspected based on strong regional clustering, higher prevalence among female family members of ICP patients, and the predisposition of ICP patients to develop intrahepatic cholestasis or cholestatic liver disease with other hormonal problems such as oral contraception. The heterogeneous state of the MDR3 gene defect may represent a genetic predisposition.

Gallstone disease

[00100] Gallstone disease is one of the most common and costly of all digestive diseases, with a prevalence of up to 17% in Caucasian women. Cholesterol-containing gallstones are the main form of gallstones, so cholesterol supersaturation of bile is a prerequisite for gallstone formation. ABCB4 mutations may be involved in the pathogenesis of cholesterol gallstone disease.

Drug-induced cholestasis

[00101] Inhibition of BSEP function by drugs is an important mechanism of drug-induced cholestasis leading to accumulation of bile salts in the liver and subsequent liver cell injury. Several drugs are involved in the inhibition of BSEP. Most of these drugs, such as rifampin, cyclosporine, glibenclamide or troglitazone, directly cis-inhibit the ATP-dependent transport of taurocholate in a competitive manner, while estrogen and progesterone metabolites indirectly trans-inhibit BSEP after secretion into the bile duct via Mrp2. Alternatively, drug-mediated stimulation of MRP2 may contribute to cholestasis or cholestatic liver disease by altering the composition of bile.

Generalized cholestasis associated with parenteral nutrition

[00102] TPNAC represents one of the most serious clinical scenarios in which cholestasis or cholestatic liver disease occurs rapidly and is closely associated with early death. Infants, who are typically premature and have had bowel resection, depend on TPN for growth and often develop cholestasis or cholestatic liver disease that rapidly progresses to fibrosis, cirrhosis, and portal hypertension, usually before 6 months of age. The degree of cholestasis or cholestatic liver disease and the chance of survival in these infants have been associated with the number of septic episodes, likely initiated by repeated bacterial translocation across the intestinal mucosa. Although these infants also have cholestatic effects from intravenous administration of the compound, septic mediators likely contribute most to the altered liver function.

Alagille syndrome (ALGS)

[00103] Alagille syndrome is a genetic disorder that affects the liver and other organs. ALGS is also known as intrahepatic bile duct insufficiency syndrome or arteriohepatic dysplasia. ALGS is a rare genetic disorder in which the bile ducts are abnormally narrow, poorly formed, and reduced in number, leading to bile accumulation in the liver and ultimately progressive liver disease. ALGS is autosomal dominant, caused by mutations in JAG1 (>90% of cases) or NOTCH2. The incidence of ALGS is estimated to be 1 in every 30,000 or 50,000 births in the United States and Europe. In patients with ALGS, the mutation may affect multiple organ systems, including the liver, heart, kidneys, and central nervous system. The buildup of bile acids prevents the liver from properly removing waste from the bloodstream and leads to progressive liver disease that eventually requires a liver transplant in 15-47% of patients. Signs and symptoms of liver damage in ALGS may include jaundice, itching, and xanthomas, as well as poor growth. The itching experienced by patients with ALGS is among the most severe of any chronic liver disease and is present in most affected children by their third year of life.

[00104] ALGS often presents in infancy (eg, 6-18 months of age) to early childhood (eg, 3-5 years of age) and may stabilize after 10 years of age. Symptoms may include chronic progressive cholestasis, ductopenia, jaundice, pruritus, xanthomas, congenital heart defects, paucity of intrahepatic bile ducts, poor linear growth, hormone resistance, posterior embryotoxon, Axenfeld anomaly, retinitis pigmentosa, pupillary abnormalities, heart murmur, atrial septal defect, ventricular septal defect, patent ductus arteriosus, and tetralogy. Individuals diagnosed with Alagille syndrome have received ursodiol, hydroxyzine, cholestyramine, rifampin, and phenobarbitol. Because of the decreased ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are additionally prescribed high-dose multivitamins.

Biliary atresia

[00105] Biliary atresia is a life-threatening condition in infants in which the bile ducts inside or outside the liver do not have normal openings. In biliary atresia, bile is retained, builds up, and damages the liver. The damage leads to scarring, loss of liver tissue, and cirrhosis. Without treatment, the liver eventually fails, and the infant requires a liver transplant to survive. There are two types of biliary atresia: fetal and perinatal. Fetal biliary atresia occurs while the baby is in the womb. Perinatal biliary atresia is much more common and does not become apparent until 2 to 4 weeks after birth.

Biliary atresia after Kasai procedure

[00106] Biliary atresia is treated with a surgical procedure called the Kasai procedure, or liver transplant. The Kasai procedure is usually the first treatment for biliary atresia. During the Kasai procedure, a pediatric surgeon removes the infant's damaged bile ducts and lifts a loop of intestine to replace them. Although the Kasai procedure can restore bile flow and correct many of the problems caused by biliary atresia, the surgery does not cure biliary atresia. If the Kasai procedure is unsuccessful, infants typically require a liver transplant within 1 to 2 years. Even with successful surgery, most infants with biliary atresia slowly develop cirrhosis over the years and require a liver transplant by adulthood. Potential complications from the Kasai procedure include ascites, bacterial cholangitis, portal hypertension, and pruritus.

Biliary atresia after liver transplantation

[00107] If the atresia is complete, liver transplantation is the only option. Although liver transplantation is usually successful in treating biliary atresia, liver transplantation can have complications such as organ rejection. A donor liver may also not be available. Additionally, in some patients, liver transplantation may not be helpful in treating biliary atresia.

Xanthoma

[00108] Xanthomas are a skin condition associated with cholestatic liver disease, in which certain fats accumulate under the surface of the skin. Cholestasis results in several lipid metabolism disorders, resulting in the formation of an abnormal lipid particle in the blood called lipoprotein X. Lipoprotein X is formed by the regurgitation of bile lipids into the blood from the liver and does not bind to the LDL receptor to deliver cholesterol to cells throughout the body like normal LDL. Lipoprotein X increases cholesterol production in the liver fivefold and blocks the liver from removing lipoprotein particles from the blood normally.

General definitions

[00109] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[00110] In this specification and the appended claims, the singular forms include the plural unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods and/or steps of the type described herein and/or that will become apparent to those skilled in the art after reading this disclosure.

[00111] As used herein, the term "baseline" or "pre-administration baseline" refers to information collected at the beginning of a study or to an initial known value that is used for comparison with later data. A baseline is an initial measurement of a measurable condition that is taken at an early time point and is used for comparison over time to look for changes in the measurable condition. For example, the concentration of bile acids in a patient's serum before drug administration (baseline) and after drug administration. A baseline is an observation or value that represents the normal or initial level of a measurable quality that is used for comparison with values that represent a response to an intervention or environmental exposure. A baseline is the "zero" time before study participants receive an experimental treatment or intervention, or a negative control. For example, "baseline" may refer in some cases to 1) the state of the measurand immediately before the start of a clinical trial or 2) the state of the measurand immediately before a change in the dosage or composition administered to a patient from a first dosage or composition to a second dosage or composition.

[00112] As used herein, the terms "content" and "concentration" are used interchangeably. For example, "high serum bilirubin content" may alternatively be stated as "high serum bilirubin concentrations."

[00113] As used herein, the terms "normalized" or "normal range" refer to age-specific values that are within a range consistent with a healthy individual (i.e., normal or normalized values). For example, the phrase "serum bilirubin concentrates were normalized within three weeks" means that the serum bilirubin concentrations are within a range known in the art and consistent with a healthy individual (i.e., within a normal range, rather than, for example, in an elevated range) within three weeks. In various embodiments, the normalized serum bilirubin concentration is from about 0.1 mg/dL to about 1.2 mg/dL. In various embodiments, the normalized serum bile acid concentration is from about 0 μmol/L to about 25 μmol/L.

[00114] As used herein, the terms "ITCHRO(OBS)" and "ITCHRO" (alternatively, "ItchRO(Pt)") are interchangeable with the qualification that the ITCHRO(OBS) scale is used to measure the severity of pruritus in children under 18 years of age, and the ITCHRO scale is used to measure the severity of pruritus in adults over 18 years of age. Therefore, when the ITCHRO(OBS) scale is referred to in relation to an adult patient, the ITCHRO scale is referred to as the scale. Likewise, whenever the ITCHRO scale is referred to in relation to a pediatric patient, the ITCHRO(OBS) scale is generally referred to (some older children were allowed to indicate their own scores as ITCHRO scores). The ITCHRO(OBS) scale ranges from 0 to 4, and the ITCHRO scale ranges from 0 to 10.

[00115] As used herein, the term "bile acid" or "bile acids" includes steroid acids (and/or their carboxylate anion) and salts thereof found in the bile of an animal (e.g., a human), including, by way of non-limiting example, cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholic acid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid, taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, tauroursodeoxycholic acid, glycoursodeoxycholic acid, 7-B-methylcholic acid, methyllithocholic acid, chenodeoxycholate, lithocholic acid, lithocholate, and the like. Taurocholic acid and/or taurocholate are referred to herein as TCA. Any reference to a bile acid used herein includes a reference to a bile acid, one and only one bile acid, one or more bile acids, or at least one bile acid. Accordingly, the terms "bile acid", "bile salt", "bile acid/salt", "bile acids", "bile salts" and "bile acids/salts" are used interchangeably herein unless otherwise specified. Any reference to a bile acid used herein includes a reference to a bile acid or a salt thereof. Additionally, pharmaceutically acceptable esters of bile acids are optionally used as the "bile acids" described herein, such as bile acids/salts conjugated with an amino acid (e.g., glycine or taurine). Other bile acid esters include, for example, substituted or unsubstituted alkyl ester, substituted or unsubstituted heteroalkyl esters, substituted or unsubstituted aryl esters, substituted or unsubstituted heteroaryl esters, and the like. For example, the term "bile acid" includes cholic acid conjugated with either glycine or taurine: glycocholate and taurocholate, respectively (and salts thereof). Any reference to a bile acid used herein includes a reference to the identical compound, whether naturally or synthetically produced. Furthermore, it should be understood that any reference in the singular to a component (bile acid or other) used herein includes a reference to one and only one, one or more, or at least one of such components. Similarly, any multiple reference to a component used herein includes reference to one and only one, one or more, or at least one of such components, unless otherwise indicated.

[00116] The term "subject," "patient," "participant," or "individual" are used interchangeably herein and refer to mammals and non-mammalian organisms, such as those suffering from a disorder described herein. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other species of monkeys and apes; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, guinea pigs, and the like. Examples of non-mammalian animals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[00117] As used herein, the term “approximately” includes any value that is within 10% of the described value.

[00118] As used herein, the term "composition" includes the disclosure of both the composition and the composition administered by the method described herein. Furthermore, in some embodiments, a composition of the present invention is or includes a "formulation," an oral dosage form, or a rectal dosage form, as described herein.

[00119] The terms "treat" or "treatment" and other grammatical equivalents as used herein include alleviating, suppressing, or reducing symptoms, reducing or suppressing severity, reducing frequency, reducing or suppressing recurrence, delaying onset, delaying recurrence, easing or alleviating symptoms of a disease or condition, eliminating underlying causes of symptoms, inhibiting a disease or condition such as stopping the progression of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or cessation of symptoms of a disease or condition. These terms also include achieving a therapeutic effect. A therapeutic effect is understood to mean eliminating or improving the underlying disorder being treated and/or eliminating or improving one or more physiological symptoms associated with the underlying disorder such that the patient experiences an improvement.

[00120] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of at least one administered agent (e.g., a therapeutically active agent) to achieve a desired result in a subject or individual, such as to alleviate to some extent one or more symptoms of a disease or condition being treated. In some cases, the result is a reduction and/or amelioration of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. In some cases, an "effective amount" for therapeutic applications is the amount of a composition containing an agent as described herein necessary to provide a clinically significant reduction in the disease. A suitable "effective" amount in any individual case is determined using any suitable method, such as a dose escalation study. In some embodiments, a "therapeutically effective amount" or "effective amount" of an ASBTI refers to a sufficient amount of an ASBTI to treat cholestasis or cholestatic liver disease in a subject or individual.

[00121] As used herein, the terms "administer," "administering," and the like refer to methods that can be used to provide delivery of agents or compositions to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Routes of administration that are optionally used with the agents and methods described herein can be found in references such as Goodman and Oilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition). Mack Publishing Co., Easton, Pa., all of which are incorporated herein by reference in their entireties for all purposes. In some embodiments, the agents and compositions described herein are administered orally.

[00122] The term "ASBT inhibitor" refers to a compound that inhibits apical sodium-dependent bile transport or any recuperative transport of bile salts. The term apical sodium-dependent bile transporter (ASBT) is used interchangeably with the term ileal bile transporter (IBAT).

[00123] The phrase "pharmaceutically acceptable" as used in connection with the compositions of the present invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and generally do not produce adverse reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[00124] In various embodiments, pharmaceutically acceptable salts described herein include, but are not limited to, nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, subsalicylate, maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-toluenesulfonate, mesylate, and the like. Additionally, pharmaceutically acceptable salts include, but are not limited to, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), ammonium salts, and the like.

Bile acid

[00125] Bile contains water, electrolytes, and many organic molecules, including bile acids, cholesterol, phospholipids, and bilirubin. Bile is secreted from the liver and stored in the gallbladder, and when the gallbladder contracts due to the ingestion of fatty foods, bile passes through the bile duct into the intestine.

Bile acids/salts are characterized by their critical importance for the digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adults produce between 400 and 800 ml of bile daily. Bile secretion can be considered to occur in two stages. Initially, hepatocytes secrete bile into canaliculi from which it flows into the bile ducts, and this liver bile contains large quantities of bile acids, cholesterol, and other organic molecules. Then, as bile flows through the bile ducts, it is modified by the addition of a watery, bicarbonate-rich secretion from the epithelial cells of the ducts. During storage in the gallbladder, bile is typically concentrated fivefold.

[00126] Bile flow is lowest during fasting, and most bile is diverted to the gallbladder for concentration. As chyme from the ingested food enters the small intestine, acids and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, which are important in the secretion and flow of bile. Cholecystokinin (cholecysto = gallbladder and kinin = movement) is a hormone that stimulates contraction of the gallbladder and common bile duct, resulting in the delivery of bile to the intestine. The most potent stimulus for the release of cholecystokinin is the presence of fat in the duodenum. Secretin is a hormone secreted in response to acid in the duodenum, and it mimics the bile duct cells to produce bicarbonate and water, which increases the volume of bile and increases its flow into the intestine.

[00127] Bile acids/salts are derivatives of cholesterol. Cholesterol ingested in the diet or synthesized in the liver is converted to bile acids/salts in the hepatocytes. Examples of such bile acids/salts include cholic acid and chenodeoxycholic acid, which are then conjugated with an amino acid (such as glycine or taurine) to form a conjugated form that is actively secreted into the tubules. The most common bile salts in humans are cholate and deoxycholate, and they are typically conjugated with either glycine or taurine to form glycocholate or taurocholate, respectively.

[00128] Free cholesterol is virtually insoluble in aqueous solutions, but it becomes soluble in bile due to the presence of bile acids/salts and lipids. Hepatic synthesis of bile acids/salts accounts for the majority of cholesterol breakdown in the body. In humans, approximately 500 mg of cholesterol is converted to bile acids/salts and excreted in bile each day. Therefore, biliary secretion is the major route of cholesterol elimination. Large quantities of bile acids/salts are secreted into the intestine each day, but only relatively small amounts are excreted from the body. This is because approximately 95% of the bile acids/salts delivered to the duodenum are reabsorbed into the blood in the ileum through a process known as "enterohepatic recirculation".

[00129] Venous blood from the ileum goes directly into the portal vein and hence through the liver sinusoids. Hepatocytes are very efficient at extracting bile acids/salts from sinusoidal blood, with a small fraction passing from the healthy liver into the systemic circulation. The bile acids/salts are then transported through the hepatocytes for re-secretion into the tubules. The net effect of this enterohepatic recycling is that each bile salt molecule is reused approximately 20 times, often two or three times during a single digestive phase. Bile biosynthesis is the major metabolic fate of cholesterol, accounting for more than half of the approximately 800 mg/day of cholesterol that the average adult uses in metabolic processes. By comparison, steroid hormone biosynthesis consumes only approximately 50 mg of cholesterol per day. Much more than 400 mg of bile salts are required and secreted into the intestine per day, and this is achieved by recycling of bile salts. Most of the bile salts secreted into the upper small intestine are absorbed along with the dietary lipids they have emulsified at the lower end of the small intestine. They are separated from the dietary lipids and returned to the liver for reuse. Thus, recycling allows 20-30 g of bile salts to be secreted into the small intestine daily.

[00130] Bile acids/salts are amphipathic, with the cholesterol-derived portion containing both hydrophobic (fat-soluble) and polar (hydrophilic) portions, while the amino acid conjugate is generally polar and hydrophilic. This amphipathic nature allows bile acids/salts to perform two important functions: emulsification of lipid aggregates and solubilization and transport of lipids in aqueous media. Bile acids/salts have a detergent effect on dietary fat particles, resulting in the breakdown or emulsification of the fat globules. Emulsification is important because it greatly increases the surface area of the fat available for digestion by lipases, which are unable to enter the lipid droplets. In addition, bile acids/salts are lipid carriers and are able to solubilize many lipids by forming micelles and are critical for the transport and absorption of fat-soluble vitamins.

[00131] As used herein, the term "non-systemic" or "minimally absorbed" refers to low systemic bioavailability and/or absorption of the administered compound. In some embodiments, a non-systemic compound is a compound that is substantially not absorbed systemically. In some embodiments, the ASBTI compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum rather than systemically (e.g., a significant portion of the ASBTI is not absorbed systemically). In some embodiments, the systemic absorption of the non-systemic compound is <0.1%, <0.3%, <0.5%, <0.6%, <0.7%, <0.8%, <0.9%, <1%, <1.5%, <2%, <3%, or <5% of the administered dose (wt% or mol%). In some embodiments, the systemic absorption of the non-systemic compound is <10% of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is <15% of the administered dose. In some embodiments, the systemic absorption of the non-systemic compound is <25% of the administered dose. In an alternative approach, the non-systemic ASBTI is a compound that has lower systemic bioavailability than the systemic bioavailability of a systemic ASBTI (e.g., compound 100A, 100C). In some embodiments, the bioavailability of a non-systemic ASBTI described herein is <30%, <40%, <50%, <60%, or <70% of the bioavailability of a systemic ASBTI (e.g., compound 100A, 100C).

[00132] In another alternative approach, the compositions described herein are formulated to systemically deliver <10% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <20% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <30% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <40% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <50% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <60% of the administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <70% of the administered dose of ASBTI. In some embodiments, systemic absorption is determined by any suitable method, including the total amount in the bloodstream, the amount excreted after administration, etc.

[00133] The term "optionally substituted" or "substituted" means that the specified group is substituted with one or more additional groups. In some embodiments, the one or more additional groups are individually and independently selected from amide, ester, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, ester, alkyl sulfone, arylsulfone, cyano, halogen, alkoyl, alkoyloxo, isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy, fluoroalkyl, amino, alkylamino, dialkylamino, amido.

[00134] An "alkyl" group refers to an aliphatic hydrocarbon group. Reference to an alkyl group includes "saturated alkyl" and/or "unsaturated alkyl." An alkyl group, saturated or unsaturated, includes branched, linear, or cyclic groups. By way of example only, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. In some embodiments, alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. "Lower alkyl" is C ₁ -C ₆ alkyl. A "heteroalkyl" group replaces any of the carbon atoms of an alkyl group with a heteroatom having the appropriate number of hydrogen atoms attached (e.g., a _CH2 group with an NH group or an O group).

[00135] The term "alkylene" refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. In one aspect, the alkylene is C ₁ -C ₁₀ alkylene. In another aspect, the alkylene is C ₁ -C ₆ alkylene. Typical alkylene groups _include , _without limitation, _-CH2- , -CH( _CH3 )-, _{-C ( CH3} ) _2- , -CH2CH2-, -CH2CH( _CH3 ) _- , _{-CH2C ( CH3} ) _{2- ,} -CH2CH2CH2-, _{-CH2CH2CH2CH2- , -CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2CH2- , -CH2CH2CH2CH2CH2CH2- , and the like .}

[00136] An "alkoxy" group refers to an (alkyl)O- group, wherein alkyl is defined as defined herein.

[00137] The term "alkylamine" refers to the group -N(alkyl) _x H _y , wherein alkyl is defined as defined herein, and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, optionally form a cyclic ring system.

[00138] An "amide" is a chemical moiety with the formula -C(O)NHR or -NHC(O)R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon).

[00139] The term "ester" refers to a chemical moiety of the formula C(=O)OR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, and heteroalicyclic.

[00140] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl rings described herein include rings containing five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups are optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl.

[00141] The term "aromatic" refers to a planar ring having a calcified π-electron system containing 4n+2π: electrons, where n is an integer. Aromatic rings may be composed of five, six, seven, eight, nine, ten, or more than ten atoms. Aromatic hydrocarbons are optionally substituted. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or polycyclic fused ring groups (i.e., rings that share adjacent pairs of carbon atoms).

[00142] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical wherein each of the atoms forming the ring (i.e., the skeletal atoms) is a carbon atom. In various embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are fused to an aromatic ring. Cycloalkyl groups include those containing from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

[00143] and the like. Monocyclic cycloalkyls include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[00144] The term "heterocyclo" refers to heteroaromatic and heteroalicyclic groups containing one to four ring heteroatoms, each of which is selected from O, S and N. In some cases, each heterocyclic group contains from 4 to 10 atoms in its ring system, and also provided that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups containing 3 atoms in their ring system, but aromatic heterocyclic groups must contain at least 5 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. An example of a 3-membered heterocyclic group is aziridinyl (derived from aziridine). An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrotyranyl, dihydrotiranyl pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl.

[00145] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal ring atoms is a nitrogen atom. In some embodiments, heteroaryl groups are monocyclic or polycyclic. Illustrative examples of heteroaryl groups include the following moieties:

etc.

[00146] A "heteroalicyclic" group or "heterocyclo" group refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. In various embodiments, the radicals are aryl or heteroaryl. Illustrative examples of heterocyclo groups, also referred to as non-aromatic heterocycles, include:

etc. The term heteroalicyclic also includes all ring forms of carbohydrates, including, without limitation, monosaccharides, disaccharides and oligosaccharides.

[00147] The term "halo" or, alternatively, "halogen" means fluorine, chlorine, bromine and iodine.

[00148] The terms "haloalkyl" and "haloalkoxy" include alkyl and alkoxy structures that are substituted with one or more halogens. In embodiments in which more than one halogen is included in the group, the halogens are the same or different. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halogen is fluorine.

[00149] The term "heteroalkyl" includes optionally substituted alkyl, alkenyl, and alkynyl radicals that contain one or more backbone atoms selected from an atom other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. In some embodiments, the heteroatom(s) are at any internal position of the heteroalkyl group. Examples include, without limitation, _-CH2 -O- _CH3 , _-CH2 - _CH2 -O- _CH3 , _-CH2 -NH- _CH3 , _-CH2 - _CH2 -NH- _CH3 , _-CH2 -N( _CH3 ) _-CH3 , -CH2 _{- CH2} -NH- _CH3 , _-CH2 - _CH2 -N( _CH3 ) _-CH3 , -CH2 _- S- _CH2 - _CH3 , _-CH2 - _CH2 ,-S(O) _-CH3 , _-CH2 - _CH2 -S(O) ₂ - _CH3 , -CH=CH-O- _CH3 , -Si( _CH3 ) ₃ , _-CH2 -CH=N- _OCH3 , and CH=CH-N( _CH3 ) _-CH3 . In some embodiments, up to two heteroatoms are sequential, such as _-CH2- NH- _OCH3 and _-CH2 -O-Si( _CH3 ) ₃ .

[00150] The cyano group belongs to the -CN group.

[00151] The isocyanato group belongs to the -NCO group.

[00152] The thiocyanate group belongs to the -CNS group.

[00153] The "isothiocyanato" group belongs to the -NCS group.

[00154] "Alkoyloxy" refers to the group RC(=O)O-.

[00155] "Alcoyl" refers to the RC(=O)- group.

[00156] As used herein, the term "modulate" refers to some influence (e.g., increasing, enhancing, or maintaining a certain level).

[00157] The term "optionally substituted" or "substituted" means that said group may be substituted with one or more additional groups individually and independently selected from _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, aryl, heteroaryl, _C2 - _C6 heteroalicyclic, hydroxy, _C1 - _C6 alkoxy, aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy, _C1 - _C6 alkylthio, arylthio, _C1 - _C6 alkylsulfoxide, arylsulfoxide, _C1 - _C6 alkylsulfone, arylsulfone, cyano, halogen, _C2 - _C8 acyl, _C2 - _C8 acyloxy, nitro, _C1 - _C6 haloalkyl, _C1 - _C6 fluoroalkyl and amino, including _C1 - _C6- alkylamino and protected derivatives thereof. As an example, the optional ^substituents can be ^LsRs , where each ^Ls is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O) _2- , -NH-, -NHC(=O)-, -C(=O)NH-, S(=O) _2NH- , -NHS(=O) _2- , -OC(=O)NH-, -NHC(=O)O-, -( _C1 - _C6 -alkyl)- or -( _C2 - _C6- alkenyl)-; and each ^Rs is independently selected from H, ( _C1 - _C4 -alkyl), ( _C3 - _C8 -cycloalkyl), heteroaryl, aryl and _C1 - _C6- heteroalkyl. Optionally substituted non-aromatic groups may be substituted with one or more oxo (=O). Protecting groups that can form protective derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts, supra. In some embodiments, the alkyl groups described herein are optionally substituted with O that is bonded to two adjacent carbon atoms (i.e., forming an epoxide).

ASBT inhibitors

[00158] According to various embodiments of the methods of the present invention, ASBT inhibitors are administered to a subject. ASBT inhibitors (ASBTIs) reduce or inhibit bile acid recirculation in the distal gastrointestinal (GI) tract, including the distal ileum, colon, and/or rectum. Inhibition of apical sodium-dependent bile acid transport interrupts enterohepatic circulation of bile acids and results in more bile acids being excreted in the feces, see Fig. 1, which results in a systemic reduction in bile acids, thereby reducing bile acid-mediated liver injury and associated effects and complications. In some embodiments, ASBTIs are absorbed systemically. In some embodiments, ASBTIs are not absorbed systemically. In some embodiments, the ASBTIs described herein are modified or substituted (e.g., with a -L-K group) to be non-systemic. In some embodiments, any ASBT inhibitor is modified or substituted with one or more charged groups (e.g., K) and, optionally, one or more linkers (e.g., L), wherein L and K are as defined herein.

[00159] According to some embodiments, an ASBTI useful in the methods described herein is a compound of Formula I:

[00160]

[00161] where:

[00162] R ¹ is a C _1-6 alkyl group with a straight chain;

[00163] R ² is a C _1-6 alkyl group with a straight chain;

[00164] R ³ is hydrogen or an OR ¹¹ group in which R ¹¹ is hydrogen optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00165] R ⁴ is pyridyl or optionally substituted phenyl or L _z -K _z ; wherein z is 1, 2 or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; each K is a group that prevents systemic absorption;

[00166] R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and are each selected from hydrogen, halogen, cyano, R ⁵ -acetylide, OR ¹⁵ optionally substituted with C _1-6 -alkyl, COR ¹⁵ , CH(OH)R ¹⁵ , S(O) _n R ¹⁵ , P(O)(OR ¹⁵ ) ₂ , OCOR ¹⁵ , OCF ₃ , OCN, SCN, NHCN, CH ₂ OR ¹⁵ , CHO, (CH ₂ ) _p CN, CONR ¹² R ¹³ , (CH ₂ ) _p CO ₂ R ¹⁵ , (CH ₂ ) _p NR ¹² R ¹³ , CO ₂ R ¹⁵ , NHCOCF ₃ , NHSO ₂ R ¹⁵ , OCH ₂ OR ¹⁵ , OCH=CHR ¹⁵ , O(CH ₂ CH ₂ O) _n R ¹⁵ , O(CH ₂ ) _p SO ₃ R ¹⁵ , O(CH ₂ ) pNR ¹² R ¹³ , O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ and WR ³¹ , where W is O or NH and R ³¹ is selected from

And

[00167] And

[00168] where p is an integer from 1 to 4, n is an integer from 0 to 3 and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from hydrogen and optionally substituted C _1-6 -alkyl; or

[00169] R ⁶ and R ⁷ are linked to form a group

[00170]

[00171] where R ¹² and R ¹³ are characterized by the values indicated above, am is 1 or 2; and

[00172] R ⁹ and R ¹⁰ are the same or different and each is selected from hydrogen or C _1-6 -alkyl; and

[00173] its salts, solvates and physiologically functional derivatives.

[00174] According to some embodiments of the methods described herein, the compound of Formula I is a compound,

[00175] in which

[00176] R ¹ is a C _1-6 straight-chain alkyl group;

[00177] R ² is a C _1-6 alkyl group with a straight chain;

[00178] R ³ is hydrogen or an OR ¹¹ group in which R ¹¹ is hydrogen optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00179] R ⁴ is optionally substituted phenyl;

[00180] R ⁵ , R ⁶ and R ⁸ are independently selected from hydrogen, C _1-4 -alkyl optionally substituted with fluoro, C _1-4 -alkoxy, halogen or hydroxy;

[00181] R ⁷ is selected from halogen, cyano, R ¹⁵ -acetylide, OR ¹⁵ , optionally substituted C _1-6 -alkyl, COR ¹⁵ , CH(OH)R ¹⁵ , S(O) _n R ¹⁵ , P(O)(OR ¹⁵ ) ₂ , OCOR ¹⁵ , OCF ₃ , OCN, SCN, HNCN, CH ₂ OR ¹⁵ , CHO, (CH ₂ ) _p CN, CONR ¹² R ¹³ , (CH ₂ ) _p CO ₂ R ¹⁵ , (CH ₂ ) _p NR ¹² R ¹³ , CO ₂ R ¹⁵ , NHCOCF ₃ , NHSO ₂ R ¹⁵ , OCH ₂ OR ¹⁵ , OCH=CHR ¹⁵ , O(CH ₂ CH ₂ O) _p R ¹⁵ , O(CH ₂ ) _p SO ₃ R ¹⁵ , O(CH ₂ ) _p NR ¹² R ¹³ and O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ ;

[00182] where n, p and R ¹² -R ¹⁵ are characterized by the above-mentioned values;

[00183] provided that at least two of R ⁵ -R ⁸ are not hydrogen; and

[00184] solvates of salts and their physiologically functional derivatives.

[00185] According to some embodiments of the methods described herein, the compound of Formula I is a compound,

[00186] in which

[00187] R ¹ is a C _1-6 alkyl group with a straight chain;

[00188] R ² is a C _1-6 straight-chain alkyl group;

[00189] R ³ is hydrogen or an OR ¹¹ group in which R ¹¹ is hydrogen optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00190] R ⁴ is unsubstituted phenyl;

[00191] R ⁵ is hydrogen or halogen;

[00192] R ⁶ and R ⁸ are independently selected from hydrogen, C _1-4 -alkyl optionally substituted with fluoro, C _1-4 -alkoxy, halogen or hydroxy;

[00193] R ⁷ is selected from OR ¹⁵ , S(O) _n R ¹⁵ , OCOR ¹⁵ , OCF ₃ , OCN, SCN, CHO, OCH ₂ OR ¹⁵ , OCH=CHR ¹⁵ , O(CH ₂ CH ₂ O) _n R ¹⁵ , O(CH ₂ ) _p SO ₃ R ¹⁵ , O(CH ₂ ) _p NR ¹² R ¹³ and O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ , where p is an integer from 1 to 4, n is an integer from 0 to 3 and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from hydrogen and optionally substituted C _1-6 alkyl;

[00194] R ⁹ and R ¹⁰ are the same or different and each is selected from hydrogen or C _1-6 -alkyl; and

[00195] its salts, solvates and physiologically functional derivatives.

[00196] According to some embodiments of the methods, wherein the compound of Formula I is a compound,

[00197] in which

[00198] R ¹ is methyl, ethyl or n-propyl;

[00199] R ² is methyl, ethyl, n-propyl, n-butyl or n-pentyl;

[00200] R ³ is hydrogen or an OR ¹¹ group, where R ¹¹ is hydrogen optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00201] R ⁴ is unsubstituted phenyl;

[00202] R ⁵ represents hydrogen;

[00203] R ⁶ and R ⁸ are independently selected from hydrogen, C _1-4 -alkyl optionally substituted with fluoro, C _1-4 -alkoxy, halogen or hydroxy;

[00204] R ⁷ is selected from OR ¹⁵ , S(O) _n R ¹⁵ , OCOR ¹⁵ , OCF ₃ , OCN, SCN, CHO, OCH ₂ OR ¹⁵ , OCH=CHR ¹⁵ , O(CH ₂ CH ₂ O) _n R ¹⁵ , O(CH ₂ ) _p SO ₃ R ¹⁵ , O(CH ₂ ) _p NR ¹² R ¹³ and O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ , where p is an integer from 1 to 4, n is an integer from 0 to 3 and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from hydrogen and optionally substituted C _1-6 alkyl;

[00205] R ⁹ and R ¹⁰ are the same or different and each is selected from hydrogen or C _1-6 -alkyl; and salts, solvates and physiologically functional derivatives thereof.

[00206] According to some embodiments of the methods, the compound of Formula I is a compound,

[00207] in which

[00208] R1 is methyl, ethyl or n-propyl;

[00209] R ² is methyl, ethyl, n-propyl, n-butyl or n-pentyl;

[00210] R ³ is hydrogen or an OR ¹¹ group, where R ¹¹ is hydrogen optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00211] R ⁴ is unsubstituted phenyl;

[00212] R ⁵ represents hydrogen;

[00213] R ⁶ is C _1-4 -alkoxy, halogen or hydroxy;

[00214] R ⁷ is OR ¹⁵ , wherein R ¹⁵ is hydrogen or optionally substituted C _1-6 -alkyl;

[00215] R ⁸ represents hydrogen or halogen;

[00216] R ⁹ and R ¹⁰ are the same or different and each is selected from hydrogen or C _1-6 -alkyl; and salts, solvates and physiologically functional derivatives thereof.

[00217] According to some embodiments of the methods, the compound of Formula I is (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide; (3R,5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (3R,5R)-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol-1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-ol-1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-8-ol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-ol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-thiol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-sulfonic acid 1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (±)-trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide hydrochloride; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-carbaldehyde-1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol-1,1-dioxide; (RS)-3,3-diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; (±)-trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4-ol-1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,7,8-triol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-ol-1,1-dioxide; 3,3-diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-8-ol-1,1-dioxide; 3,3-dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-ol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate or 3,3-diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl hydrogen sulfate.

[00218] According to some embodiments, the compound of Formula I is

or

[00219] According to some embodiments of the methods, the compound of Formula I is

[00220] According to some embodiments, the compound of Formula I does not have the structure shown as:

[00221] where m is an integer of 1 or 2, and R ³ and R ⁴ , which may be mutually different, each represent an alkyl group containing from 1 to 5 carbon atoms.

[00222] In some embodiments, an ASBTI useful in the methods described herein is a compound of Formula II.

[00223] where:

[00224] q is an integer from 1 to 4;

[00225] n is an integer between 0 and 2;

[00226] R ¹ and R ² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl and cycloalkyl,

[00227] wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl and cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹⁰ R ^w A ^- , SR ⁹ , S ⁺ R ⁹ R ¹⁰ A ^- , P ⁺ R ⁹ R ¹⁰ R ¹¹ A ^- , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ,

[00228] wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl and cycloalkyl optionally contain one or more carbon atoms replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ^- , S, SO, SO ₂ , S ⁺ R ⁹ A ^- , P ⁺ R ⁹ R ¹⁰ A ^- or phenylene,

[00229] where R ⁹ , R ¹⁰ and R ^w are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl and alkylammonium alkyl; or

[00230] R1 and ^R2 , taken together with the carbon atom to which they are attached, form _C3 - _C10 -cycloalkyl;

[00231] R ³ and R ⁴ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ , wherein R ⁹ and R ¹⁰ are as defined above; or

[00232] R ³ and R ⁴ together represent =O, =NOR ¹¹ , =S, =NNR ¹¹ R ¹² , =NR ⁹ or =CR ¹¹ R ¹² ,

[00233] wherein R ¹¹ and R ¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenyl alkyl, alkynyl alkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00234] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00235] R ⁵ and R ⁶ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ and -L _z -K _z ;

[00236] wherein z is 1, 2, or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a group that prevents systemic absorption;

[00237] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle and quaternary heteroaryl may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R ¹⁵ , OR ¹³ , OR ¹³ R ¹⁴ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C(O)NR ¹³ R ¹⁴ , C(O)OM, CR ¹³ , P(O)R ¹³ R ¹⁴ , P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ^- , P(OR ¹³ )OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A ^- and N ⁺ R ⁹ R ¹¹ R ¹² A ^- ,

[00238] where:

[00239] A ^- is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may be further substituted with one or more substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , S(O)R ⁷ , SO ₂ R ⁷ , SO ₃ R ⁷ , CO ₂ R ⁷ , CN, oxo, CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ^- , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary P(O)R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P(O)(OR ⁷ )OR ⁸ and

[00240] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and ^heterocycle may optionally have one or more carbon atoms replaced with O, ^NR7 , N ^{+ R7R8A- ,} S, SO, _SO2 , S ^{+ R7A- , PR7} , P(O ^{) R7} , P ^{+ R7R8A-} or ^phenylene , and ^R13 , ^R14 and ^R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl and GTVW,

[00241] wherein the alkyl, alkenyl, alkynyl, arylalkyl, heterocycle and polyalkyl optionally have one or more carbon atoms replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ^- , S, SO, SO ₂ , S ⁺ R ⁹ A ^- , PR, P ⁺ R ⁹ R ¹⁰ A ^- , P(O)R ⁹ , phenylene, carbohydrate, C ₂ -C ₇ polyol, amino acid, peptide or polypeptide, and

[00242] G, T and V each independently represent a bond, -O-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -C(O)N(H)-, -N(H)C(O)-, -N(H)C(O)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl or substituted or unsubstituted cycloalkyl, and

[00243] W is a quaternary heterocycle, a quaternary heteroaryl, a quaternary heteroarylalkyl, N ⁺ R ⁹ R ¹¹ R ¹² A ^- , P ⁺ R ⁹ R ¹⁰ R ¹¹ A ^- , OS(O) ₂ OM, or S ⁺ R ⁹ R ¹⁰ A ^- , and

[00244] R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO(OR ¹⁶ )OR ¹⁷ , P ⁺ R ⁹ R ¹⁰ R ¹¹ A ^- , S ⁺ R ⁹ R ¹⁰ A ^- and C(O)OM,

[00245] where R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M;

or

[00246] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and

[00247] is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and

[00248] R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; and

[00249] one or more R ^x are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , S(O) ₂ R ¹³ , SO ₃ R ¹³ , S ⁺ R ¹³ R ¹⁴ A ^- , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C(O)R ¹³ , C(O)NR ¹³ R ¹⁴ , NR ¹⁴ C(O)R ¹³ , C(O)OM, COR ¹³ , OR ¹⁸ , S(O) _n NR ¹⁸ , NR ¹³ R ¹⁸ , NR ¹⁸ R ¹⁴ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , P ⁺ R ⁹ R ¹¹ R ¹² A ^- , amino acids, peptides, polypeptides and carbohydrates,

[00250] wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle and quaternary heteroaryl may be further substituted with OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO(OR ¹⁶ )OR ¹⁷ , P ⁺ R ⁹ R ¹¹ R ¹² A ^- , S ⁺ R ⁹ R ¹⁰ A ^- or C(O)M, and

[00251] where R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

[00252] wherein the acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₃ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO(OR ¹⁶ )OR ¹⁷ and C(O)OM,

[00253] wherein in R ^x one or more carbon atoms are optionally replaced by O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ^- , S, SO, SO ₂ , S ⁺ R ¹³ A ^- , PR ¹³ , P(O)R ¹³ , P ⁺ R ¹³ R ¹⁴ A ^- , phenylene, an amino acid, a peptide, a polypeptide, a carbohydrate, a polyether or a polyalkyl,

[00254] wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide and carbohydrate one or more carbon atoms are optionally replaced by O, NR ⁹ , R ⁹ R ¹⁰ A ^- , S, SO, SO ₂ , S ⁺ R ⁹ A ^- , PR ⁹ , P ⁺ R ⁹ R ¹⁰ A ^- or P(O)R ⁹ ;

[00255] wherein the quaternary heterocycle and the quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C(O)NR ¹³ R ¹⁴ , C(O)OM, COR ¹³ , P(O)R ¹³ R ¹⁴ P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ^- , P(OR ¹³ )OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A ^- and N ⁺ R ⁹ R ¹¹ R ¹² A ^- ,

[00256] provided that both R ⁵ and R ⁶ cannot be hydrogen or SH;

[00257] provided that when R ⁵ or R ⁶ is phenyl, only one of R ¹ or R ² is H;

[00258] provided that when q=1 and R ^x is styryl, anilido or anilinocarbonyl, only one of R ⁵ or R ⁶ is alkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00259] According to some embodiments of the methods, the compound of Formula II is a compound wherein

[00260] q is an integer from 1 to 4;

[00261] n is 2;

[00262] R ¹ and R ² are independently selected from the group consisting of H, alkyl, alkoxy, dialkylamino and alkylthio,

[00263] wherein alkyl, alkoxy, dialkylamino and alkylthio are optionally substituted with one or more substituents selected from the group consisting of OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , SO ₂ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ;

[00264] each R ⁹ and R ¹⁰ is each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, acyl, heterocycle, and arylalkyl;

[00265] R ³ and R ⁴ are independently selected from the group consisting of H, alkyl, acyloxy, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ and SO ₂ R ⁹ , wherein R ⁹ and R ¹⁰ are as defined above;

[00266] R ¹¹ and R ¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00267] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00268] R ⁵ and R ⁶ are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, heterocycle, and -L _z -K _z ;

[00269] wherein z is 1 or 2; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a group that prevents systemic absorption;

[00270] wherein alkyl, aryl, cycloalkyl and heterocycle may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR ¹³ , OR ¹³ R ¹⁴ , NR ¹³ R ¹⁴ , SR ¹³ , SO ₂ R ¹³ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM and CR ¹³ ,

[00271] where:

[00272] A ^is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation;

[00273] R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl and quaternary heteroarylalkyl, wherein R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one or more groups selected from the group consisting of quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , SR ⁹ , S(O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen and CONR ⁹ R ¹⁰ ; or

[00274] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and

[00275] is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and

[00276] R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; and

[00277] one or more R ^x are independently selected from the group consisting of H, alkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S(O) ₂ R ¹³ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C(O)R ¹³ , C(O)NR ¹³ R ¹⁴ , NR ¹⁴ C(O)R ¹³ and COR ¹³ ;

[00278] provided that both R ⁵ and R ⁶ cannot be hydrogen;

[00279] provided that when R ⁵ or R ⁶ is phenyl, only one of R ¹ or R ² is H;

[00280] provided that when q=1 and R ^x is styryl, anilido or anilinocarbonyl, only one of R ⁵ or R ⁶ is alkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00281] According to some embodiments, the compound of Formula II is a compound in which

[00282] q is 1;

[00283] n is 2;

[00284] R ^x is N(CH ₃ ) ₂ ;

[00285] R ⁷ and R ⁸ independently represent H;

[00286] R ¹ and R ² are alkyl;

[00287] R ³ is H, and R ⁴ is OH;

[00288] R ⁵ is H, and R ⁶ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ and -L _z -K _z ;

[00289] wherein z is 1, 2, or 3; each L is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each K is a group that prevents systemic absorption;

[00290] wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle and quaternary heteroaryl may be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R ¹⁵ , OR ¹³ , OR ¹³ R ¹⁴ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C(O)NR ¹³ R ¹⁴ , C(O)OM, CR ¹³ , P(O)R ¹³ R ¹⁴ , P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ^- , P(OR ¹³ )OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A ^- and N ⁺ R ⁹ R ¹¹ R ¹² A ^- ,

[00291] where ^A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may be further substituted with one or more substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , S(O)R ⁷ , SO ₂ R ⁷ , SO ₃ R ⁷ , CO ₂ R ⁷ , CN, oxo, CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ^- , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heterocycle, P(O)R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P(O)(OR ⁷ ) OR ⁸ and

[ ^{00292] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may optionally be characterized in that one or more carbon atoms are replaced by O, NR7, N + R7R8A- , S , SO} , _SO2 , S ^{+ R7A- , PR7} , P(O ^{) R7} , P ^{+ R7R8A-} or ^phenylene , and ^R13 , ^R14 and ^R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl and -GTVW,

[00293] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle and polyalkyl are optionally characterized in that one or more carbon atoms are replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ^- , S, SO, SO ₂ , S ⁺ R ⁹ A ^- , PR, P ⁺ R ⁹ R ¹⁰ A ^- , P(O)R ⁹ , phenylene, carbohydrate, C ₂ -C ₇ polyol, amino acid, peptide or polypeptide and

[00294] G, T and V are each independently a bond, -O-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -O-alkyl, -N(H)-alkyl, -C(O)N(H)-, -N(H)C(O)-, -N(H)C(O)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl or substituted or unsubstituted cycloalkyl, and

[00295] W is a quaternary heterocycle, a quaternary heteroaryl, a quaternary heteroarylalkyl, N ⁺ R ⁹ R ¹¹ R ¹² A ^- , P ⁺ R ⁹ R ¹⁰ R ¹¹ A ^- , OS(O) ₂ OM, or S ⁺ R ⁹ R ¹⁰ A ^- , and

[00296] R ⁹ and R ¹⁰ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl, and alkylammonium alkyl;

[00297] R ¹¹ and R ¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00298] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00299] R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , SR ⁹ , S(O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO(OR ¹⁶ )OR ¹⁷ , P ⁺ R ⁹ R ¹⁰ R ¹¹ A ^- , S ⁺ R ⁹ R ¹⁰ A ^- and C(O)OM,

[00300] where R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M; or

[00301] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl and arylalkyl;

[00302] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00303] According to some embodiments, the compound of Formula II is a compound in which

[00304] q is 1;

[00305] n is 2;

[00306] R ^x is N(CH ₃ ) ₂ ;

[00307] R ⁷ and R ⁸ independently represent H;

[00308] R ¹ and R ² are independently C ₁ -C ₄ alkyl;

[00309] R ³ is H, and R ⁴ is OH;

[00310] R ⁵ is H, and R ⁶ is aryl substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, R ¹⁵ , OR ¹³ , OR ¹³ R ¹⁴ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C(O)NR ¹³ R ¹⁴ , C(O)OM, CR ¹³ , P(O)R ¹³ R ¹⁴ , P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ^- , P(OR ¹³ )OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A ^- and N ⁺ R ⁹ R ¹¹ R ¹² A ^- ,

[00311] where ^A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may be further substituted with one or more substituent groups selected from the group consisting of OR ⁷ , NR ⁷ R ⁸ , S(O)R ⁷ , SO ₂ R ⁷ , SO ₃ R ⁷ , CO ₂ R ⁷ , CN, oxo, CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ^- , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P(O)(OR ⁷ ) OR ⁸ , and

[00312] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, ^{aryl, haloalkyl, cycloalkyl and heterocycle may optionally be characterized in that one or more carbon atoms are replaced by O, NR7, N + R7R8A- , S , SO} , _SO2 , S ^{+ R7A- , PR7} , P(O ^{) R7} , P ^{+ R7R8A-} or ^phenylene , and ^R13 , ^R14 and ^R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl and GTVW,

[00313] wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle and polyalkyl are optionally characterized in that one or more carbon atoms are replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ^- , S, SO, SO ₂ , S ⁺ R ⁹ A ^- , PR, P ⁺ R ⁹ R ¹⁰ A ^- , P(O)R ⁹ , phenylene, carbohydrate, C ₂ -C ₇ polyol, amino acid, peptide or polypeptide and

[00314] G, T and V are each independently a bond, -O-, -S-, -N(H)-, substituted or unsubstituted alkyl, -O-alkyl, -N(H)-alkyl, -C(O)N(H)-, -N(H)C(O)-, -N(H)C(O)N(H)-, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted carboxyalkyl, substituted or unsubstituted carboalkoxyalkyl or substituted or unsubstituted cycloalkyl, and

[00315] W is a quaternary heterocycle, a quaternary heteroaryl, a quaternary heteroarylalkyl, N ⁺ R ⁹ R ¹¹ R ¹² A ^- , P ⁺ R ⁹ R ¹⁰ R ¹¹ A-, OS(O) ₂ OM, or S ⁺ R ⁹ R ¹⁰ A ^- , and

[00316] R ⁹ and R ¹⁰ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;

[00317] R ¹¹ and R ¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00318] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00319] R ¹³ , R ¹⁴ and R ¹⁵ are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , SR ⁹ , S(O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO(OR ¹⁶ )OR ¹⁷ , P ⁺ R ⁹ R ¹⁰ R ¹¹ A ^- , S ⁺ R ⁹ R ¹⁰ A ^- and C(O)OM,

[00320] where R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M; or

[00321] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl and arylalkyl;

[00322] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00323] According to some embodiments of the methods, the compound of formula II is a compound,

[00324] in which

[00325] R ⁵ and R ⁶ are independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl.

[00326] wherein aryl, heteroaryl, quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , OR ¹³ R ¹⁴ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C(O)NR ¹³ R ¹⁴ , C(O)OM, COR ¹³ , P(O)R ¹³ R ¹⁴ P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ^- , P(OR ¹³ )OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A ^- , N ⁺ R ⁹ R ¹¹ R ¹² A ^- and -L _z -K _z .

[00327] According to some embodiments of the methods, the compound of Formula II is a compound,

[00328] in which

[00329] R ⁵ or R ⁶ is -Ar-(R ^y ) _t

[00330] t is an integer between 0 and 5;

[00331] Ar is selected from the group consisting of phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, oxazolotriazolyl, isoxazolyl, pyrimolinyl, isoxazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzoisothiazolyl; and

[00332] one or more R ^y are independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , OR ¹³ R ¹⁴ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C(O)NR ¹³ R ¹⁴ , C(O)OM, COR ¹³ , P(O)R ¹³ R ¹⁴ P ⁺ R ¹³ R ¹⁴ R ¹⁵ A ^- , P(OR ¹³ )OR ¹⁴ , S ⁺ R ¹³ R ¹⁴ A ^- , N ⁺ R ⁹ R ¹¹ R ¹² A ^- and -L _z -K _z ;

[00333] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may be further substituted with one or more substituent groups selected from the group consisting of OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S(O)R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, oxo, CONR ⁷ R ⁸ , N ⁺ R ⁷ R ⁸ R ⁹ A ^- , alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ A ^- , and P(O)(OR ⁷ )OR ⁸ and/or phenylene;

[00334] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may optionally be characterized in that one or more carbon atoms are replaced by O, NR ⁷ , N ⁺ R ⁷ R ⁸ A ^- , S, SO, SO ₂ , S ⁺ R ⁷ A ^- , PR ⁷ , P(O)R ⁷ , P ⁺ R ⁷ R ⁸ A ^- or phenylene.

[00335] According to some embodiments of the methods, the compound of Formula II is a compound in which

[00336] R ⁵ or R ⁶ is

[00337]

[00338] In some embodiments of the methods, the compound of Formula II is a compound wherein n is 1 or 2. In some embodiments of the methods, the compound of Formula II is a compound wherein R ¹ and R ² are independently H or C _1-7 alkyl. In some embodiments of the methods, the compound of Formula II is a compound wherein each C _1-7 alkyl is independently ethyl, n-propyl, n-butyl, or isobutyl. In some embodiments of the methods, the compound of Formula II is a compound wherein R ³ and R ⁴ are independently H or OR ⁹ . In some embodiments of the methods, the compound of Formula II is a compound wherein R ⁹ is H

[00339] In some embodiments of the methods, the compound of Formula II is a compound in which one or more R ^x is at position 7, 8, or 9 of the benzene ring of Formula II. In some embodiments of the methods, the compound of Formula II is a compound in which R ^x is at position 7 of the benzene ring of Formula II. In some embodiments of the methods, the compound of Formula II is a compound in which one or more R ^x is independently selected from OR ¹³ and NR ¹³ R ¹⁴ .

[00340] According to some embodiments of the methods, the compound of Formula II is a compound,

[00341] in which:

[00342] q is 1 or 2;

[00343] n is 2;

[00344] R ¹ and R ² each represent alkyl;

[00345] R ³ is hydroxy;

[00346] R ⁴ and R ⁶ represent hydrogen;

[00347] R ⁵ is characterized by the formula

[00348]

[00349] where

[00350] t is an integer between 0 and 5;

[00351] one or more RY is OR ¹³ or OR ¹³ R ¹⁴ ;

[00352] R ¹³ and R ¹⁴ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl;

[00353] wherein said alkyl, alkenyl, alkynyl, arylalkyl, heterocyclic and polyalkyl groups are optionally characterized in that one or more carbon atoms are replaced by O, NR ⁹ , N ⁺ R ⁹ R ¹⁰ A ^- , S, SO, SO ₂ , S ⁺ R ⁹ A ^- , PR ⁹ , P ⁺ R ⁹ R ¹⁰ A ^- , P(O)R ⁹ , phenylene, a carbohydrate, an amino acid, a peptide or a polypeptide;

[00354] R ¹³ and R ¹⁴ are optionally substituted with one or more groups independently selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR ⁹ , NR ⁹ R ¹⁰ , N ⁺ R ⁹ R ¹¹ R ¹² A ^- , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO2R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO(OR ¹⁶ )OR ¹⁷ , P ⁺ R ⁹ R ¹⁰ R ¹¹ A-, S ⁺ R ⁹ R ¹⁰ A ^- and C(O)OM,

[00355] where A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,

[00356] R ⁹ and R ¹⁰ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, arylalkyl, and alkylammonium alkyl;

[00357] R ¹¹ and R ¹² are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S(O)R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that both R ³ and R ⁴ cannot be OH, NH ₂ and SH; or

[00358] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and

[00359] R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M;

[00360] R ⁷ and R ⁸ represent hydrogen; and

[00361] one or more R ^x are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino, and -WR ³¹ , wherein W is O or NH, and R ³¹ is selected from

[00362] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00363] According to some embodiments, the compound of formula II is (maralixibat),

or or etc.

[00364] According to some embodiments of the methods, the compound of Formula II is

[00365]

[00366] In certain embodiments, ASBTIs useful in the methods described herein are non-systemic analogs of compound 100C. Certain compounds provided herein are analogs of compound 100C that are modified or substituted to include a charged group. In particular embodiments, analogs of compound 100C are modified or substituted with a charged group that is an ammonium group (e.g., a cyclic or acyclic ammonium group). In some embodiments, the ammonium group is a non-protic ammonium group that contains a quaternary nitrogen.

[00367] According to some embodiments, the compound of Formula II is

[00368]

[00369] According to some embodiments, the compound of Formula II is 1-[[5-[[3-[(3S,4R,5R)-3-3-butyl-7-(dimethylamino)-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5yl]phenyl]amino]-5-oxopentyl]amino]-1-deoxy-D-glucitol or SA HMR1741 (also known as BARI-1741).

[00370] According to some embodiments, the compound of Formula II is

[00371]

[00372] According to some embodiments, the compound of Formula II is potassium ((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]ureido}-3,5-dihydroxytetrahydropyran-2-ylmethyl)sulfate ethanolate, hydrate, or SAR548304B (also known as SAR-548304).

[00373] According to some embodiments, an ASBTI useful in the methods described herein is a compound of Formula III:

[00374]

[00375] where:

[00376] each R ¹ , R ² is independently H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or LK; or R ¹ and R ² , together with the nitrogen to which they are attached, form a 3-8 membered ring that is optionally substituted with R ⁸ ;

[00377] each R ³ , R ⁴ is independently H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or LK;

[00378] R ⁵ is H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl,

[00379] each R ⁶ , R ⁷ is independently H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or LK; or R ⁶ and R ⁷ taken together form a bond;

[00380] each X is independently NH, S or O;

[00381] each Y is independently NH, S or O;

[00382] R ⁸ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or -LK;

[00383] L is A _n , where

[00384] each A is independently NR ¹ , S(O) _m , O, C(=X)Y, Y(C=X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; wherein each m is independently 0-2;

[00385] n is 0-7;

[00386] K is a group that prevents systemic absorption;

[00387] provided that at least one of R ¹ , R ² , R ³ or R ⁴ is -LK;

[00388] or a pharmaceutically acceptable prodrug thereof.

[00389] In some embodiments of the compound of Formula III, R ¹ and R ³ are -LK. In some embodiments, R ¹ , R ² and R ³ are -LK.

[00390] In some embodiments, at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is H. In some embodiments, R ⁵ , R ⁶ , R ⁷ are H and R ¹ , R ² , R ³ and R ⁴ are alkyl, aryl, alkylaryl, or heteroalkyl. In some embodiments, R ¹ and R ² are H. In some embodiments, R ¹ , R ² , R ⁵ , R ⁶ and R ⁷ are H. In some embodiments, R ⁶ and R ⁷ together form a bond. In some embodiments, R ⁵ , R ⁶ and R ⁷ are H, alkyl, or O-alkyl.

[00391] In some embodiments, R ¹ and R ³ are -LK. In some embodiments, R ¹ , R ² and R ³ are -LK. In some embodiments, R ³ and R ⁴ are -LK. In some embodiments, R ¹ and R ² , together with the nitrogen to which they are attached, form a 3-8 membered ring, and the ring is substituted with -LK. In some embodiments, R ¹ or R ² or R ³ or R ⁴ is aryl optionally substituted with -LK. In some embodiments, R ¹ or R ² or R ³ or R ^{4 is alkyl optionally substituted with -LK. In some embodiments, R 1 or R 2 or R 3 or R 4 is alkylaryl optionally substituted} with -LK. In some embodiments, R ¹ or R ² or R ³ or R ⁴ is heteroalkyl optionally substituted with -LK.

[00392] In some embodiments, L is _C1 - _C7 -alkyl. In some embodiments, L is heteroalkyl. In some embodiments, L is _C1 - _C7 -alkylaryl. In some embodiments, L is _C1 - _C7- alkylaryl- _C1 - _C7- alkyl.

[00393] In certain embodiments, K is a non-protic charged group. In some specific embodiments, each K is an ammonium group. In some embodiments, each K is a cyclic non-protic ammonium group. In some embodiments, each K is an acyclic non-protic ammonium group.

[00394] According to certain embodiments, each K is a cyclic non-protic ammonium group of the structure:

[00395] According to certain embodiments, K is an acyclic non-protic ammonium group of the structure:

[00396] where p, q, R ⁹ , R ¹⁰ and Z are as defined above. In some embodiments, p is 1. In other embodiments, p is 2. In further embodiments, p is 3. In some embodiments, q is 0. In other embodiments, q is 1. In some other embodiments, q is 2.

[00397] The compounds further comprise 1, ² , 3, or 4 anionic counterions selected from ^Cl- , Br- ^{, I-} , _R11SO3- ^, ( _SO3 ^{-- R11} _{-SO3-), R11CO2-, (CO2--R11CO2-), (R11)2 (} ^{P =} _O ^{) O- , and (} _R11 ^{) ( P} =O) _O22- , wherein ^R11 is as defined above. In some embodiments _, the counterion is _Cl- ^, Br- ^, I- ^, _{CH2CO2- , CH3SO3-, or C6H5SO3- or} ^{CO2 --} ₍ ^CH2 _{) 2 -CO2- .} ^In some embodiments ^, the compound _of Formula III comprises one K group and one _counterion . In other embodiments, the compound of Formula III comprises one K group and two molecules of the compound of Formula III comprise one counterion. In yet other embodiments, the compound of Formula III comprises two K groups and two counterions. In some other embodiments, the compound of Formula III comprises one K group comprising two ammonium groups and two counterions.

[00398] The present document also describes compounds characterized by

Formula IIIA:

[00399] where:

[00400] each R ¹ , R ² is independently H, substituted or unsubstituted alkyl, or -LK; or R ¹ and R ² together with the nitrogen to which they are attached form a 3-8 membered ring that is optionally substituted with R ⁸ ;

[00401] and R ³ , R ⁴ , R ⁸ , L and K are characterized by the meanings indicated above.

[00402] According to some embodiments of the compounds of Formula IIIA, L is _An , wherein each A is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl, and n is 0-7. In certain specific embodiments of the compounds of Formula IIIA, R ¹ is H. In some embodiments of Formula IIIA, R ¹ and R ^2, together with the nitrogen to which they are attached, form a 3-8 membered ring that is optionally substituted with -LK.

[00403] The present document also describes compounds characterized by

Formula IIIB:

[00404] where:

[00405] each R ³ , R ⁴ is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, or -LK;

[00406] and R ¹ , R ² , L and K are characterized by the values indicated above.

[00407] In certain embodiments of Formula IIIB, R ³ is H. In some embodiments, R ³ and R4 are each -LK. In some embodiments, R ³ is H and R ⁴ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl containing one or two -LK groups.

[00408] In some embodiments, an ASBTI useful in the methods described herein is a compound of Formula IIIC.

[00409]

[00410] where:

[00411] each R ¹ , R ² is independently H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or -LK; or R ¹ and R ^2, together with the nitrogen to which they are attached, form a 3- to 8-membered ring that is optionally substituted with R ⁸ ;

[00412] each R ³ , R ⁴ is independently H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or -LK;

[00413] R ⁵ is H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl,

[00414] each R ⁶ , R ⁷ is independently H, hydroxy, alkyl, alkoxy, -C(=X)YR ⁸ , -YC(=X)R ⁸ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl or -LK; or R ⁶ and R ⁷ taken together form a bond;

[00415] each X is independently NH, S or O;

[00416] each Y is independently NH, S or O;

[00417] R ⁸ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylcycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl, or -LK;

[00418] L is A _n , where

[00419] each A is independently NR ¹ , S(O) _m , O, C(=X)Y, Y(C=X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; wherein each m is independently 0-2;

[00420] n is 0-7;

[00421] K is a group that prevents systemic absorption;

[00422] or a pharmaceutically acceptable salt thereof.

[00423] According to some specific embodiments of Formula I, II or III, K is selected from

[00424]

[00425] According to some embodiments, an ASBTI useful in the methods described herein is a compound of Formula IV:

[00426]

[00427] where

[00428] R ¹ is a C _1-6 alkyl group with a straight chain;

[00429] R ² is a C _1-6 alkyl group with a straight chain;

[00430] R ³ is hydrogen or an OR ¹¹ group, where R ¹¹ is hydrogen optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00431] R ⁴ is pyridyl or optionally substituted phenyl;

[00432] R ⁵ , R ⁶ and R ⁸ are the same or different and each is selected from:

[00433] hydrogen, halogen, cyano, R ¹⁵ -acetylide, OR ¹⁵ , optionally substituted C _1-6 -alkyl, COR ¹⁵ , CH(OH)R ¹⁵ , S(O) _n R ¹⁵ , P(O)(OR ¹⁵ ) ₂ , OCOR ¹⁵ , OCF ₃ , OCN, SCN, NHCN, CH ₂ OR ¹⁵ , CHO, (CH ₂ ) _p CN, CONR ¹² R ¹³ , (CH ₂ ) _p CO ₂ R ¹⁵ , (CH ₂ ) _p NR ¹² R ¹³ , CO ₂ R ¹⁵ , NHCOCF ₃ , NHSO ₂ R ¹⁵ , OCH ₂ OR ¹⁵ , OCH=CHR ¹⁵ , O(CH ₂ CH ₂ O) _n R ¹⁵ , O(CH ₂ ) _p SO ₃ R ¹⁵ , O(CH ₂ ) _p NR ¹² R ¹³ and O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ , where

[00434] p is an integer from 1 to 4,

[00435] n is an integer between 0 and 3 and

[00436] R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from hydrogen and optionally substituted C _1-6 -alkyl;

[00437] R ⁷ is a group of the formula

[00438]

[00439]

[00440]

[00441] where the hydroxyl groups can be substituted by acetyl, benzyl,

[00442] or -(C ₁ -C ₆ )-alkyl-R ¹⁷ ,

[00443] wherein the alkyl group may be substituted by one or more hydroxyl groups;

[00444] R ¹⁶ is -COOH, -CH ₂ -OH, -CH ₂ -O-acetyl, -COOMe or -COOEt;

[00445] R ¹⁷ is H, -OH, NH ₂ , COOH or COOR ¹⁸ ;

[00446] R ¹⁸ is (C ₁ -C ₄ )-alkyl or -NH-(C ₁ -C ₄ )-alkyl;

[00447] X is -NH- or -O-; and

[00448] R ⁹ and R ¹⁰ are the same or different and each represents hydrogen or C ₁ -C ₆ -alkyl; and salts thereof.

[00449] According to some embodiments, a compound of Formula IV is characterized by a structure of forms of Formula IVA or Formula IVB:

[00450]

[00451]

[00452] According to some embodiments, the compound of Formula IV is characterized by the structure of Formula IVC:

[00453]

[00454] According to some embodiments of Formula IV, X is O and R ⁷ is selected from

[00455]

[00456] According to some embodiments, the compound of Formula IV is:

[73]

[00458] According to some embodiments, an ASBTI useful in the methods described herein is a compound of Formula V:

[00459]

[00460]

[00461] where:

[00462] R ^v is selected from hydrogen or C _1-6 -alkyl;

[00463] One of R ¹ and R ² is selected from hydrogen or C _1-6 -alkyl, and the other is selected from C _1-6 -alkyl;

[00464] R ^x and R ^y are independently selected from hydrogen, hydroxy, amino, mercapto, C _1-6 -alkyl, C _1-6 -alkoxy, N-(C _1-6 -alkyl)amino, N,N-(C _1-6 -alkyl) ₂ -amino, C _1-6 -alkylS(O) _a , where a is from 0 to 2;

[00465] R ^z is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _1-6 -alkoxy, C _1-6 -alkanoyl, C _1-6 -alkanoyloxy, N-(C _1-6 -alkyl)amino, N,N-(C _1-6 -alkyl) ₂ -amino, C _1-6 -alkanoylamino, N-(C _1-6 -alkyl)carbamoyl, N,N-(C _1-6 -alkyl) ₂ -carbamoyl, C _1-6 -alkylS(O) _a , where a is from 0 to 2, C _1-6 -alkoxycarbonyl, N-(C _1-6 -alkyl)sulfamoyl and N,N-(C _1-6 -alkyl) ₂ -sulfamoyl;

[00466] n is 0-5;

[00467] one of R ⁴ and R ⁵ is a group of formula (VA):

[00468]

[00469] R ³ and R ⁶ and the other of R ⁴ and R ⁵ are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N-(C _1-6 alkyl)amino, N,N-(C _1-6 alkyl) ₂ -amino, C _1-6 alkanoylamino, N-(C _1-6 alkyl)carbamoyl, N,N-(C _1-6 alkyl) ₂ -carbamoyl, C _1-6 alkylS(O) _a , where a is 0-2, C _1-6 -alkoxycarbonyl, N-(C _1-6 -alkyl)sulfamoyl and N,N-(C _1-6 -alkyl) ₂ -sulfamoyl;

[00470] wherein R ³ and R ⁶ and the other of R ⁴ and R ⁵ may be optionally substituted on a carbon atom by one or more R ¹⁷ ;

[00471] X is -O-, -N(R ^a )-, -S(O) ^b -, or -CH(R ^a )-

[00472] where R ^a is hydrogen or C _1-6 -alkyl, ab is 0-2;

[00473] ring A is aryl or heteroaryl;

[00474] wherein ring A is optionally substituted on a carbon atom with one or more substituents selected from R ¹⁸ ;

[00475] R ⁷ is hydrogen, C _1-6 -alkyl, carbocyclyl or heterocyclyl;

[00476] wherein R ⁷ is optionally substituted on a carbon atom with one or more substituents selected from R ¹⁹ ; and wherein, if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted with a group selected from R ²⁰ ;

[00477] R ⁸ is hydrogen or C _1-6 -alkyl;

[00478] R ⁹ is hydrogen or C _1-6 -alkyl;

[00479] R ¹⁰ is hydrogen, halogen, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkynyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N-(C _1-10 alkyl)amino, N,N-(C _1-10 alkyl) ₂ -amino, N,N,N-(C _1-10 alkyl) ₃ -ammonio, C _1-10 alkanoylamino, N-(C _1-10 alkyl)carbamoyl, N,N-(C _1-10 alkyl) ₃ -carbamoyl, C _1-10 -alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 alkyl)sulfamoyl, N,N-(C _1-10 alkyl) ₂ -sulfamoyl, N-(C _1-10 alkyl)sulfamoylamino, N,N-(C _1-10 alkyl) ₂ -sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclyl-C _1-10 alkyl, heterocyclyl, heterocyclyl-C _1-10 alkyl, carbocyclyl(C _1-10 alkylene) _p -R ^21- (C _1-10 alkylene) _q- or heterocyclyl(C _1-10 alkylene) _r -R ^22- (C _1-10 alkylene) _s- ; wherein R ¹⁰ is optionally substituted on a carbon atom by one or more substituents selected from R ²³ ; and wherein, if said heterocyclyl contains a group -NH-, this nitrogen may be optionally substituted by a group selected from R ²⁴ ; or R ¹⁰ is a group of formula (VB):

[00480]

[00481] where:

[00482] R ¹¹ is hydrogen or C _1-6 -alkyl;

[00483] R ¹² and R ¹³ are independently selected from hydrogen, halogen, carbamoyl,

sulfamoyl, C _1-10 alkyl, C _2-10 alkynyl, C _2-10 alkynyl, C _1-10 alkanoyl, N-(C _1-10 alkyl)carbamoyl, N,N-(C _1-10 alkyl) ₂ -carbamoyl, C _1-10 alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 alkyl)sulfamoyl, N,N-(C _1-10 alkyl) ₂ -sulfamoyl, N-(C _1-10 alkyl)sulfamoylamino, N,N-(C _1-10 alkyl) ₂ -sulfamoylamino, carbocyclyl or heterocyclyl; wherein R ¹² and R ¹³ may independently be optionally substituted on a carbon atom with one or more substituents selected from R ²⁵ ; and wherein if said heterocyclyl contains a -NH- group, this nitrogen may be optionally substituted with a group selected from R ²⁶ ;

[00484] R ¹⁴ is selected from hydrogen, halogen, carbamoyl, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkanoyl, N-(C _1-10 alkyl)carbamoyl, N,N-(C _1-10 alkyl) ₂ -carbamoyl, C _1-10 alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 alkyl)sulfamoyl, N,N-(C _1-10 alkyl) ₂ -sulfamoyl, N-(C _1-10 alkyl)sulfamoylamino, N,N-(C _1-10 alkyl) ₂ -sulfamoylamino, carbocyclyl, carbocyclyl-C _1-10 -alkyl, heterocyclyl, heterocyclyl-C _1-10- alkyl, carbocyclyl(C _1-10 -alkylene) _p -R ²⁷ -(C _1-10 -alkylene) _q - or heterocyclyl(C _1-10 -alkylene) _r -R ²⁸ -(C _1-10 -alkylene)s-; wherein R ¹⁴ is optionally substituted on the carbon atom by one or more substituents selected from R ²⁹ ; and wherein if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted by a group selected from R ³⁰ ; or R ¹⁴ is a group of formula (VC):

[00485]

[00486] R ¹⁵ is hydrogen or C _1-6 alkyl; and R ¹⁶ is hydrogen or C _1-6 alkyl; wherein R ¹⁶ may be optionally substituted on the carbon atom by one or more groups selected from R ³¹ ;

[00487] or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclyl; said heterocyclyl being optionally substituted on a carbon atom by one or more R ³⁷ ; and wherein if said heterocyclyl contains an -NH- group, that nitrogen may be optionally substituted by a group selected from R ³⁸ ;

[00488] m is equal to 13; and the values of R ⁷ may be the same or different;

[00489] R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ , R ³¹ and R ³⁷ are independently selected from halogen, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N-(C _1-10 alkyl)amino, N,N-(C _1-10 alkyl) ₂ -amino, N,N,N-(C _1-10 alkyl) 3 -ammonio, C _1-10 alkanoylamino, N-(C _1-10- alkyl)carbamoyl, N,N-(C _1-10 -alkyl) ₂ -carbamoyl, C _1-10 -alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 -alkyl)sulfamoyl, N,N-(C _1-10 -alkyl) ₂ -sulfamoyl, N-(C _1-10 -alkyl)sulfamoylamino, N,N-(C _1-10 -alkyl) ₂ -sulfamoylamino, C _1-10 -alkoxycarbonylamino, carbocyclyl, carbocyclyl-C _1-10 -alkyl, heterocyclyl, heterocyclyl-C _1-10 -alkyl, carbocyclyl(C _1-10 -alkylene) _p -R ³² -(C _1-10 -alkylene)q- or heterocyclyl(C _1-10 -alkylene) _r -R ³³ -(C _1-10 -alkylene)s-; wherein R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ , R ³¹ and R ³⁷ may be independently optionally substituted on a carbon atom by one or more R ³⁴ ; and wherein if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted with a group selected from R ³⁵ ;

[00490] R ²¹ , R ²² , R ²⁷ , R ²⁸ , R ³² or R ³³ are independently selected from -O-, -NR ³⁶ -, -S(O) _x -, NR ³⁶ C(O)NR ³⁶ , -NR ³⁶ C(S)NR ³⁶ -, OC(O)N=C, -NR ³⁶ C(O)- or -C(O)NR ³⁶ -; wherein R ³⁶ is selected from hydrogen or C _1-6 alkyl and x is 0-2;

[00491] p, q, r and s are independently selected from 0-2;

[00492] R ³⁴ is selected from halogen, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-methylsulfamoylamino and N,N-dimethylsulfamoylamino;

[00493] R ²⁰ , R ²⁴ , R ²⁶ , R ³⁰ , R ³⁵ and R ³⁸ are independently selected from C _1-6 -alkyl, C _1-6 -alkanoyl, C _1-6 -alkylsulfonyl, C _1-6 -alkoxycarbonyl, carbamoyl, N-(C _1-6 -alkyl)carbamoyl, N,N-(C _1-6 -alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl; and

[00494] wherein "heteroaryl" is a fully unsaturated, mono- or bicyclic ring containing 3-12 atoms of which at least one atom is selected from nitrogen, sulfur and oxygen, wherein heteroaryl may, unless otherwise specified, be bonded to carbon or nitrogen;

[00495] wherein "heterocyclyl" is a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 3-12 atoms of which at least one atom is selected from nitrogen, sulfur and oxygen, wherein the heterocyclyl may, unless otherwise indicated, be carbon or nitrogen bonded, wherein the _-CH2- group may optionally be replaced by a -C(O)- group, and the ring sulfur atom may optionally be oxidized to form an S-oxide; and

[00496] wherein "carbocyclyl" is a saturated, partially saturated or unsaturated, mono- or bicyclic carbon ring that contains 3-12 atoms; wherein the -CH ₂ - group may optionally be replaced by a -C(O) group;

[00497] or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester or amide formed at an accessible carboxy or hydroxy group thereof.

[00498] According to some embodiments, the compound of Formula V is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulfoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-l-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(R)-α-carboxy-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine or 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine or a salt thereof.

[00499] According to some embodiments, the compound of Formula V is

[00500] or

[00501] According to some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula VI:

[00502]

[00503] where:

[00504] R ^v and R ^w are independently selected from hydrogen or C _1-6 -alkyl;

[00505] one of R ¹ and R ² is selected from hydrogen or C _1-6 -alkyl, and the other is selected from C _1-6 -alkyl;

[00506] R ^x and R ^y are independently selected from hydrogen or C _1-6 -alkyl, or one of R ^x and R ^y is hydrogen or C _1-6 -alkyl and the other is hydroxy or C _1-6 -alkoxy;

[00507] R ^z is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, C _1-6 -alkoxy, C _1-6 -alkanoyl, C _1-6 -alkanoyloxy, N-(C _1-6 -alkyl)amino, N,N-(C _1-6 -alkyl) ₂ -amino, C _1-6 -alkanoylamino, N-(C _1-6 -alkyl)carbamoyl, N,N-(C _1-6 -alkyl) ₂ -carbamoyl, C _1-6 -alkylS(O) _a , where a is from 0 to 2, C _1-6 -alkoxycarbonyl, N-(C _1-6 -alkyl)sulfamoyl and N,N-(C _1-6 -alkyl) ₂ -sulfamoyl;

[00508] n is 0-5;

[00509] one of R ⁴ and R ⁵ is a group of formula (VIA):

[00510]

[00511] R ³ and R ⁶ and the other of R ⁴ and R ⁵ are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, N-(C _1-6 alkyl)amino, N,N-(C _1-6 alkyl) ₂ -amino, C _1-6 alkanoylamino, N-(C _1-6 alkyl)carbamoyl, N,N-(C _1-6 alkyl) ₂ -carbamoyl, C _1-6 alkylS(O) _a , where a is 0-2, C _1-6 -alkoxycarbonyl, N-(C _1-6 -alkyl)sulfamoyl and N,N-(C _1-6 -alkyl) ₂ -sulfamoyl; wherein R ³ and R ⁶ and the other of R ⁴ and R ⁵ may be optionally substituted on a carbon atom by one or more R ¹⁷ ;

[00512] X is -O-, -N(R ^a )-, -S(O) _b -, or -CH(R ^a )-; where R ^a is hydrogen or C _1-6 -alkyl, ab is 0-2;

[00513] ring A is aryl or heteroaryl; wherein ring A is optionally substituted on a carbon atom with one or more substituents selected from R ¹⁸ ;

[00514] R ⁷ is hydrogen, C _1-6 -alkyl, carbocyclyl or heterocyclyl; wherein R ⁷ is optionally substituted on a carbon atom with one or more substituents selected from R ¹⁹ ; and wherein, if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted with a group selected from R ²⁰ ;

[00515] R ⁸ is hydrogen or C _1-6 -alkyl;

[00516] R ⁹ is hydrogen or C _1-6 -alkyl;

[00517] R ¹⁰ is hydrogen, halogen, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N-(C _1-10 alkyl)amino, N,N-(C _1-10 alkyl) ₂ -amino, N,N,N-(C _1-10 alkyl) ₃ -ammonio, C _1-10 alkanoylamino, N-(C _1-10 alkyl)carbamoyl, N,N-(C _1-10 alkyl) ₂ -carbamoyl, C _1-10 -alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 -alkyl)sulfamoyl, N,N-(C _1-10 -alkyl) ₂ -sulfamoyl, N-(C _1-10 -alkyl)sulfamoylamino, N,N-(C _1-10 -alkyl) ₂ -sulfamoylamino, C _1-10 -alkoxycarbonylamino, carbocyclyl, carbocyclyl-C _1-10 -alkyl, heterocyclyl, heterocyclyl-C _1-10 -alkyl, carbocyclyl(C _1-10 -alkylene) _p -R ²¹ -(C _1-10 -alkylene) _q - or heterocyclyl(C _1-10 -alkylene) _r -R ²² -(C _1-10 -alkylene) _s -; wherein R ¹⁰ is optionally substituted on a carbon atom by one or more substituents selected from R ²³ ; and wherein, if said heterocyclyl contains a group -NH-, this nitrogen may be optionally substituted by a group selected from R ²⁴ ; or R ¹⁰ is a group of formula (VIB):

[00518]

[00519] where:

[00520] R ¹¹ is hydrogen or C _1-6 -alkyl;

[00521] R ¹² and R ¹³ are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N-(C _1-10 alkyl)amino, N,N-(C _1-10 alkyl) ₂ -amino, C _1-10 alkanoylamino, N-(C _1-10 alkyl)carbamoyl, N,N-(C _1-10 alkyl) ₂ -carbamoyl, C _1-10 alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 -alkyl)sulfamoyl, N,N-(C _1-10- alkyl) ₂ -sulfamoyl, N-(C _1-10 -alkyl)sulfamoylamino, N,N-(C _1-10 -alkyl) ₂ -sulfamoylamino, carbocyclyl or heterocyclyl; wherein R ¹² and R ¹³ may independently be optionally substituted on a carbon atom with one or more substituents selected from R ²⁵ ; and wherein if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted with a group selected from R ²⁶ ;

[00522] R ¹⁴ is selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, N-(C _1-10 alkyl)amino, N,N-(C _1-10 alkyl) ₂ -amino, N,N,N-(C _1-10 alkyl) 3-ammonio, C _1-10 alkanoylamino, N-(C _1-10 alkyl) carbamoyl, N,N-(C _1-10 alkyl) ₂ -carbamoyl, C _1-10 -alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 alkyl)sulfamoyl, N,N-(C _1-10 alkyl) ₂ -sulfamoyl, N-(C _1-10 alkyl)sulfamoylamino, N,N-(C _1-10 alkyl) ₂ -sulfamoylamino, C _1-10 alkoxycarbonylamino, carbocyclyl, carbocyclyl-C _1-10 alkyl, heterocyclyl, heterocyclyl-C _1-10 alkyl, carbocyclyl(C _1-10 alkylene) _p -R ^27- (C _1-10 alkylene) _q- or heterocyclyl(C _1-10 alkylene) _r -R ^28- (C _1-10 alkylene) _s- ; wherein R ¹⁴ may be optionally substituted on a carbon atom by one or more substituents selected from R ²⁹ ; and wherein, if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted by a group selected from R ³⁰ ; or R ¹⁴ is a group of formula (VIC):

[00523]

[00524] R ¹⁵ is hydrogen or C _1-6 -alkyl;

[00525] R ¹⁶ is hydrogen or C _1-6 -alkyl; wherein R ¹⁶ may be optionally substituted on the carbon atom by one or more groups selected from R ³¹ ;

[00526] n is 1-3; wherein the values of R ⁷ may be the same or different;

[00527] R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ or R ³¹ are independently selected from halogen, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, amidino, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkanoyloxy, (C _1-10 alkyl) ₃ silyl, N-(C _1-10 alkyl) amino, N,N-(C _1-10 alkyl) ₂ -amino, N,N,N-(C _1-10 alkyl) ₃ -ammonio, C _1-10 -alkanoylamino, N-(C _1-10 -alkyl)carbamoyl, N,N-(C _1-10 -alkyl) ₂ -carbamoyl, C _1-10 -alkylS(O) _a , where a is from 0 to 2, N-(C _1-10 -alkyl)sulfamoyl, N,N-(C _1-10 -alkyl) ₂ -sulfamoyl, N-(C _1-10 -alkyl)sulfamoylamino, N,N-(C _1-10 -alkyl) ₂ -sulfamoylamino, C _1-10 -alkoxycarbonylamino, carbocyclyl, carbocyclyl-C _1-10 -alkyl, heterocyclyl, heterocyclyl-C _1-10 -alkyl, carbocyclyl(C _1-10 -alkylene) _p -R ³² -(C _1-10 -alkylene) _q - or heterocyclyl(C _1-10 -alkylene) _r -R ³³ -(C _1-10 -alkylene) _s -; wherein R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²³ , R ²⁵ , R ²⁹ or R ³¹ may be independently optionally substituted on a carbon atom by one or more R ³⁴ ; and wherein if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted by a group selected from R ³⁵ ;

[00528] R ²¹ , R ²² , R ²⁷ , R ²⁸ , R ³² or R ³³ are independently selected from -O-, -NR ³⁶ -, S(O) _x -, -NR ³⁶ C(O)NR ³⁶ -, -NR ³⁶ C(S)NR ³⁶ -, -OC(O)N=C-, -NR ³⁶ C(O)- or -C(O)NR ³⁶ -; wherein R ³⁶ is selected from hydrogen or C _1-6 alkyl and x is 0-2;

[00529] p, q, r and s are independently selected from 0-2;

[00530] R ³⁴ is selected from halogen, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl, N-methylsulfamoylamino and N,N-dimethylsulfamoylamino;

[00531] R ²⁰ , R ²⁴ , R ²⁶ , R ³⁰ or R ³⁵ are independently selected from C _1-6 -alkyl, C _1-6 -alkanoyl, C _1-6 -alkylsulfonyl, C _1-6 -alkoxycarbonyl, carbamoyl, N-(C _1-6 -alkyl)carbamoyl, N,N-(C _1-6 -alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl;

[00532] or a pharmaceutically acceptable salt, solvate, or solvate of such a salt, or an in vivo hydrolyzable ester formed at an accessible carboxy or hydroxy thereof, or an in vivo hydrolyzable amide formed at an accessible carboxy thereof.

[00533] According to some embodiments, a compound of Formula VI is characterized by a structure of Formula VID:

[00534]

[00535] where:

[00536] R ¹ and R ² are independently selected from C _1-6 -alkyl; one of R ⁴ and R ⁵ is a group of formula (VIE):

[00537]

[00538] R ³ and R ⁶ and the other of R ⁴ and R ⁵ are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N-(C _1-4 alkyl)amino, N,N-(C _1-4 alkyl) ₂ -amino, C _1-4 alkanoylamino, N-(C _1-4 alkyl)carbamoyl, N,N-(C _1-4 alkyl) ₂ -carbamoyl, C _1-4 alkylS(O) _a , where a is 0-2, C _1-4 -alkoxycarbonyl, N-(C _1-4 -alkyl)sulfamoyl and N,N-(C _1-4 -alkyl) ₂ -sulfamoyl; wherein R ³ and R ⁶ and the other of R ⁴ and R ⁵ may be optionally substituted on a carbon atom by one or more R ¹⁴ ;

[00539] R ⁷ is carboxy, sulfo, sulfino, phosphono, -P(O)(OR ^a )(OR ^b ), P(O)(OH)(OR ^a ), -P(O)(OH)(R ^a ) or P(O)(OR ^a )(R ^b ), wherein R ^a and R ^b are independently selected from C _1-6 -alkyl; or R ⁷ is a group of formula (VIF):

[83]

[00541] R ⁸ and R ⁹ are independently hydrogen, C _1-4 alkyl or a saturated cyclic group, or R ⁸ and R ⁹ together form C _2-6 alkylene; wherein R ⁸ and R ⁹ or R ⁸ and R ⁹ together may be independently optionally substituted on a carbon atom with one or more substituents selected from R ¹⁵ ; and wherein if said saturated cyclic group contains an -NH- moiety, that nitrogen may be optionally substituted with one or more R ²⁰ ;

[00542] R ¹⁰ is hydrogen or C _1-4 -alkyl; wherein R ¹⁰ is optionally substituted on the carbon atom with one or more substituents selected from R ²⁴ ;

[00543] R ¹¹ is hydrogen, C _1-4 -alkyl, carbocyclyl or heterocyclyl; wherein R ¹¹ is optionally substituted on a carbon atom with one or more substituents selected from R ¹⁶ ; and wherein, if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted with one or more R ²¹ ;

[00544] R ¹² is hydrogen or C _1-4 -alkyl, carbocyclyl or heterocyclyl; wherein R ¹² is optionally substituted on a carbon atom with one or more substituents selected from R ¹⁷ ; and wherein, if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted with one or more R ²² ;

[00545] R ¹³ is carboxy, sulfo, sulfino, phosphono, -P(O)(OR ^c )(OR ^d ), -P(O)(OH)(OR ^c ), -P(O)(OH) (R ^c ) or -P(O)(OR ^c )(R ^d ), where R ^c and R ^d are independently selected from C _1-6 alkyl;

[00546] m is equal to 1-3; wherein the values of R ⁸ and R ⁹ may be the same or different;

[00547] n is 1-3; wherein the values of R ¹¹ may be the same or different;

[00548] p is 1-3; wherein the values of R ¹² may be the same or different;

[00549] R ¹⁴ and R ¹⁶ are independently selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N-(C _1-4 alkyl)amino, N,N-(C _1-4 alkyl) ₂ -amino, C _1-4 alkanoylamino, N-(C _1-4 alkyl)carbamoyl, N,N-(C _1-4 alkyl) ₂ -carbamoyl, C _1-4 alkylS(O) _a , where a is from 0 to 2, C _1-4 alkoxycarbonyl, N-(C _1-4 -alkyl)sulfamoyl and N,N-(C _1-4 -alkyl) ₂ -sulfamoyl; wherein R ¹⁴ and R ¹⁶ may be independently optionally substituted on the carbon atom by one or more R ¹⁸ ;

[00550] R ¹⁵ and R ¹⁷ are independently selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkanoyl, C _1-4 alkanoyloxy, N-(C _1-4 alkyl)amino, N,N-(CN-alkyl) ₂ -amino, C _1-4 alkanoylamino, N-(C _1-4 alkyl)carbamoyl, N,N-(C _1-4 alkyl) ₂ -carbamoyl, C _1-4 alkylS(O) _a , where a is from 0 to 2, C _1-4 alkoxycarbonyl, N-(C _1-4 -alkyl)sulfamoyl and N,N-(C _1-4 -alkyl) ₂ -sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(OR ^e )(OR ^f ), -P(O)(OH)(OR ^e ), -P(O)(OH)(Re) or -P(O)(OR ^e )(R ^f ), wherein R ^e and R ^f are independently selected from C _1-6 -alkyl; wherein R ¹⁵ and R ¹⁷ may be independently optionally substituted on a carbon atom by one or more R ¹⁹ ; and wherein if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted by one or more R ²³ ;

[00551] R ¹⁸ , R ¹⁹ and R ²⁵ are independently selected from halogen, hydroxy, cyano, carbamoyl, ureidoaminonitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl and N,N-dimethylsulfamoyl;

[00552] ^R20 , ^R21 , ^R22 , ^R23 and ^R26 are independently _C1-4 -alkyl, _C1-4 -alkanoyl, _C1-4- alkylsulfonyl, sulfamoyl, N-( _C1-4 -alkyl)sulfamoyl, N,N-( _C1-4 -alkyl)2-sulfamoyl, _C1-4 -alkoxycarbonyl, carbamoyl, N-( _C1-4 -alkyl)carbamoyl, N,N-( _C1-4 -alkyl)2-carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl and phenyl;

[00553] R ²⁴ is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C _1-4 -alkyl, C _2-4 -alkenyl, C _2-4 -alkynyl, C _1-4 -alkoxy, C _1-4 -alkanoyl, C _1-4 -alkanoyloxy, N-(C _1-4 -alkyl)amino, N,N-(C _1-4 -alkyl)2-amino, C _1-4 -alkanoylamino, N-(C _1-4 -alkyl)carbamoyl, N,N-(C _1-4 -alkyl) ₂ -carbamoyl, C _1-4 -alkylS(O) _a , where a is from 0 to 2, C _1-4 -alkoxycarbonyl, N-(C _1-4 -alkyl)sulfamoyl and N,N-(C _1-4 -alkyl) ₂ -sulfamoyl, carbocyclyl, heterocyclyl; wherein R ²⁴ may independently be optionally substituted on a carbon atom by one or more R ²⁵ ; and wherein, if said heterocyclyl contains an -NH- group, this nitrogen may be optionally substituted by one or more R ²⁶ ;

[00554] wherein any saturated cyclic group is a fully or partially saturated mono- or bicyclic ring containing 3-12 atoms, of which 0-4 atoms are selected from nitrogen, sulfur or oxygen, which may be bonded to carbon or nitrogen;

[00555] wherein any heterocyclyl is a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 3-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, which may be bonded to carbon or nitrogen, wherein the -CH ₂ - group may optionally be replaced by -C(O)- or the ring sulfur atom may optionally be oxidized to form S-oxides; and

[00556] wherein any carbocyclyl is a saturated, partially saturated or unsaturated, mono- or bicyclic carbon ring that contains 3-12 atoms, wherein the -CH ₂ - group may optionally be replaced by -C(O)-;

[00557] or a pharmaceutically acceptable salt thereof.

[00558] According to some embodiments, the compound of Formula IV is 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine or a salt thereof.

[00559] In some embodiments, any compound described herein is covalently conjugated to a bile acid using any suitable method. In some embodiments, the compounds described herein are covalently linked to a cyclodextrin or a biodegradable polymer (e.g., a polysaccharide).

[00560] In certain embodiments, the compounds described herein are not absorbed systemically. Also provided herein are compounds that inhibit the recirculation of bile salts in the gastrointestinal tract of an individual. In some embodiments, the compounds described herein may not be transported out of the intestinal lumen and/or do not interact with ASBT. In some embodiments, the compounds described herein do not interfere or minimally interfere with fat digestion and/or absorption. In some embodiments, administration of a therapeutically effective amount of any compound described herein does not result in gastrointestinal disturbances or lactic acidosis in the individual. In some embodiments, the compounds described herein are administered orally. In some embodiments, the ASBTI is secreted in the distal ileum. An ASBTI compatible with the methods described herein may be a direct inhibitor, an allosteric inhibitor, or a partial inhibitor of the apical sodium-dependent bile acid transporter.

[00561] According to certain embodiments, compounds that inhibit ASBT or any regenerating bile acid transporters are compounds that are described in EP 1810689, U.S. Patent Nos. 6,458,851, 7,413,536, 7,514,421, U.S. Patent Application Publication Nos. 2002/0147184, 2003/0119809, 2003/0149010, 2004/0014806, 2004/0092500, 2004/0180861, 2004/0180860, 2005/0031651, 2006/0069080, 2006/0199797, 2006/0241121, 2007/0065428, 2007/0066644, 2007/0161578, 2007/0197628, 2007/0203183, 2007/0254952, 2008/0070888, 2008/0070892, 2008/0070889, 2008/0070984, 2008/0089858, 2008/0096921, 2008/0161400, 2008/0167356, 2008/0194598, 2008/0255202, 2008/0261990, WO2002/50027, WO2005/046797, WO2006/017257, WO2006/105913, WO2006/105912, WO2006/116499, WO2006/117076, WO2006/121861, WO2006/122186, WO2006/124713, WO2007/050628, WO2007/101531, WO2007/134862, WO2007/140934, WO2007/140894, WO2008/028590, WO2008/033431, WO2008/033464, WO2008/031501, WO2008/031500, WO2008/033465, WO2008/034534, WO2008/039829, WO2008/064788, WO2008/064789, WO2008/088836, WO2008/104306, WO2008/124505 and WO2008/130616; the compounds described therein that inhibit the recuperative transport of bile acids are incorporated herein by reference.

[00562] According to some embodiments, compounds that inhibit ASBT or any recuperative bile acid transporters are compounds described in WO93/16055, W094/18183, W094/18184, WO96/05188, WO96/08484, WO96/16051, W097/33882, W098/38182, W099/35135, WO98/40375, WO99/64409, WO99/64410, WO00/01687, WO00/47568, WO00/61568, DE19825804, WO00/38725, WO00/38726, WO00/38727 (including compounds with the 2,3,4,5-tetrahydro-1-benzothiepine-1,1-dioxide structure), WO00/38728, WO01/66533, WO02/50051, EP0864582 (e.g. (3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl(β-D-glucopyranosideuronic acid)), WO94/24087, WO98/07749, W098/56757, W099/32478, W099/35135, WO00/20392, WO00/20393, WO00/20410, WO00/20437, WO01/34570, WO00/35889, WO01/68637, WO01/68096, WO02/08211, WO03/020710, WO03/022825, WO03/022830, WO03/0222861, JP10072371, US Patents 5,910,494; 5,723,458; 5,817,652; 5,663,165; 5,998,400; 6,465,451, 5,994,391; 6,107,494; 6,387,924; 6,784,201; 6,875,877; 6740663; 6852753; 5070103, 6114322, 6020330, 7179792, EP251315, EP417725, EP489-423, EP549967, EP573848, EP624593, EP624594, EP624595, EP869121, EP1070703, WO04/005247, medicinal products disclosed as having IBAT activity in Drugs of the Future, 24, 425-430 (1999), Journal of Medicinal Chemistry, 48, 5837-5852, (2005) and Current Medicinal Chemistry, 13, 997-1016, (2006); The compounds described therein that inhibit the recuperative transport of bile acids are incorporated herein by reference.

[00563] In some embodiments, compounds that inhibit ASBT or any regenerating bile acid transporter are benzothiepines, benzothiazepines (including 1,2-benzothiazepines; 1,4-benzothiazepines; 1,5-benzothiazepines and/or 1,2,5-benzothiadiazepines). In some embodiments, compounds that inhibit ASBT or any regenerating bile acid transporter include, but are not limited to, S-8921 (disclosed in EP597107, WO93/08155), 264W94 (GSK) disclosed in WO96/05188; SC-435 (1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]4-aza-1-azoniabicyclo[2.2.2]octane methanesulfonate salt), SC-635 (Searle); 2164U90 (3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca); barixibate (11-(D-gluconamido)-N-{2-[(1S,2R,3S)-3-hydroxy-3-phenyl-2-(2-pyridyl)-1-(2-pyridylamino)propyl]phenyl)}undecanamide) or the like, or combinations thereof. In some embodiments, the ASBTI is:

[00564]

[00565] In certain embodiments, the compounds described herein are characterized by one or more chiral centers. As such, all stereoisomers are contemplated herein. In various embodiments, the compounds described herein are present in optically active or racemic forms. It is understood that the compounds of the present invention include racemic, optically active, regioisomeric, and stereoisomeric forms, or combinations thereof, that have the therapeutically useful properties described herein. The preparation of optically active forms is achieved by any suitable method, including, by way of non-limiting example, resolution of the racemic form by recrystallization methods, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In some embodiments, mixtures of one or more isomers are used as a therapeutic compound described herein. In some embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including enantioselective synthesis and/or separation of a mixture of enantiomers and/or diastereomers. Separation of the compounds and their isomers is achieved by any means, including, as a non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography, and the like.

[00566] According to some embodiments, the ASBTI is

[00567] (maralixibat, LUM-001, SHP625, lopixibat chloride) or its alternative pharmaceutically acceptable salt.

[00568] According to some embodiments, the ASBTI is

[00569] (volixibate, (2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenyl]ureido}-3,5-dihydroxytetrahydropyran-2-ylmethyl)hydrogen sulfate) or a pharmaceutically acceptable salt thereof.

[00570] According to some embodiments, the ASBTI is

[00571] (LUM-002; SHP626; SAR548304; volixibat potassium) or an alternative pharmaceutically acceptable salt thereof.

[00572] According to various embodiments, ASBTI is (odevixibat; AZD8294; WHO10706; AR-H064974; SCHEMBL946468; A4250; 1,1-dioxo-3,3-dibuquinol-5-phenyl-7-methylpyridin-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine) or a pharmaceutically acceptable salt thereof.

[00573] According to some embodiments, the ASBTI is (elobixibat; 2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dichloro-1λ,6,5-benzothiazepine)-8-yl)oxy]acetyl]amino]-2-phenylacetyl]amino]acetic acid) or a pharmaceutically acceptable salt thereof.

[00574] According to some embodiments, the ASBTI is (GSK2330672; linerixibat; 3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid) or a pharmaceutically acceptable salt thereof.

[00575] According to some embodiments, the ASBTI used in the methods or compositions of the present invention is maralixibat (SHP625), volixibat (SHP626), or odevixibat (A4250), or a pharmaceutically acceptable salt thereof.

[00576] According to some embodiments, the ASBTI used in the methods or compositions of the present invention is maralixibat or a pharmaceutically acceptable salt thereof.

[00577] According to some embodiments, the ASBTI used in the methods or compositions of the present invention is volixibat or a pharmaceutically acceptable salt thereof.

[00578] According to some embodiments, the ASBTI used in the methods or compositions of the present invention is odevixibat or a pharmaceutically acceptable salt thereof.

[00579] According to some embodiments, the ASBTI used in the methods or compositions of the present invention is elobixibat or a pharmaceutically acceptable salt thereof.

[00580] According to some embodiments, the ASBTI used in the methods or compositions of the present invention is GSK2330672 or a pharmaceutically acceptable salt thereof.

[00581] In some embodiments, the ASBTI may comprise a mixture of different ASBTIs; for example, the ASBTI may be a composition comprising maralixibat, volixibat, odevixibat, GSK2330672, elobixibat, or various combinations thereof.

Treatment methods for cholestasis

[00582] Provided herein is a method for treating cholestasis in a subject suffering from a liver disease. The method comprises administering to a subject in need of treatment an apical sodium-dependent bile acid transporter inhibitor (ASBTI). The ASBTI is maralixibat or volixibat, or a pharmaceutically acceptable salt thereof. The ASBTI is administered in an amount of from about 140 mcg/kg/day to about 1400 mcg/kg/day.

[00583] In various embodiments, the liver disease is a cholestatic liver disease. In some embodiments, the liver disease is PFIC, ALGS, PSC, biliary atresia, intrahepatic cholestasis of pregnancy, PBC, any of the cholestatic liver diseases described above, or various combinations thereof.

[00584] According to certain embodiments, the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFIC type 2, PFIC type 3, Alagille syndrome, Dubin-Johnson syndrome, biliary atresia, biliary atresia after the Kasai procedure, biliary atresia after liver transplantation, cholestasis after liver transplantation, liver disease associated with liver transplantation, liver disease associated with intestinal failure, bile acid-mediated liver injury, primary sclerosing cholangitis in children, MRP2 deficiency syndrome, sclerosing cholangitis of the newborn, obstructive cholestasis in children, non-obstructive cholestasis in children, extrahepatic cholestasis in children, intrahepatic cholestasis in children, primary intrahepatic cholestasis in children, secondary intrahepatic cholestasis in children, benign recurrent intrahepatic cholestasis (BRIC), BRIP type 1, BRIC type 2, BRIC type 3, generalized parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer syndrome, drug-associated cholestasis, infection-associated cholestasis, or cholelithiasis. In some embodiments, the cholestatic liver disease is a pediatric liver disease. In some embodiments, the subject has intrahepatic cholestasis of pregnancy (ICP).

[00585] According to certain embodiments, the cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hypercholesterolemia, neonatal respiratory distress syndrome, pneumonia, elevated serum bile acid levels, elevated liver bile acid levels, elevated serum bilirubin levels, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, weakness, loss of appetite, anorexia, a specific odor, dark urine, light-colored stool, steatorrhea, growth retardation, and/or renal failure.

[00586] In various embodiments, the liver disease is PFIC 2 and the subject has a non-truncating mutation in the ABCB11 gene. In various embodiments, the non-truncating mutation in the ABCB11 gene is a missense mutation. In various embodiments, the missense mutation can be selected from one of those mutations listed in Byrne, et al., "Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messanger RNA Splicing," Hepatology, 49:553-567 (2009), which is incorporated herein by reference in its entirety for all purposes.

[00587] In various embodiments, the subject has a condition associated with, caused by, or partially caused by a BSEP deficiency. In certain embodiments, the condition associated with, caused by, or partially caused by a BSEP deficiency is neonatal hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), PFIC 2, benign recurrent intrahepatic cholestasis (BRIC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, oral contraceptive-induced cholestasis, biliary atresia, or combinations thereof.

[00588] In various embodiments, the patient is a pediatric patient under the age of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 years. In certain embodiments, the pediatric patient is a newborn, a premature newborn, an infant, a toddler, a preschooler, a school-aged child, a prepubertal child, a postpubertal child, an adolescent, or an adolescent under the age of eighteen years. In some embodiments, the pediatric patient is a newborn, a premature newborn, an infant, a toddler, a preschooler, or a school-aged child. In some embodiments, the pediatric patient is a newborn, a premature newborn, an infant, a toddler, or a preschooler. In some embodiments, the pediatric patient is a newborn, a premature newborn, an infant, or a toddler. In some embodiments, the pediatric patient is a newborn, a premature newborn, or an infant. In some embodiments, the pediatric patient is a newborn. In some embodiments, the pediatric patient is an infant. In some embodiments, the pediatric patient is a toddler. In various embodiments, the pediatric patient has PFIC 2, PFIC 1, or ALGS. In some embodiments, the patient is an adult over 18, 20, 30, 40, 50, 60, or 70 years of age. In some patients, the adult patient is characterized by the presence of PSC. In some embodiments, the pediatric patient has any pediatric cholestatic condition resulting in subnormal height or weight.

[00589] According to certain embodiments, the methods of the present invention involve non-systemic administration of a therapeutically effective amount of an ASBTI. According to certain embodiments, the methods involve contacting the gastrointestinal tract, including the distal ileum and/or the colon and/or the rectum, of a human in need thereof with an ASBTI. According to various embodiments, the methods of the present invention cause a decrease in bile acid content within enterocytes or a decrease in damage to hepatocellular or intestinal architecture caused by cholestasis or cholestatic liver disease.

[00590] According to various embodiments, the methods of the present invention comprise delivering to the ileum or colon of an individual a therapeutically effective amount of any ASBTI described herein.

[00591] In various embodiments, the methods of the present invention comprise reducing damage to hepatocellular or intestinal architecture or cells from cholestasis or cholestatic liver disease, comprising administering a therapeutically effective amount of an ASBTI. In some embodiments, the methods of the present invention comprise reducing bile acid/salt content within enterocytes by administering a therapeutically effective amount of an ASBTI to an individual in need thereof.

[00592] In some embodiments, the methods of the present invention involve inhibiting bile salt recycling upon administration to an individual of any of the compounds described herein. In some embodiments, an ASBTI described herein is absorbed systemically upon administration. In some embodiments, an ASBTI described herein is not absorbed systemically. In some embodiments, an ASBTI described herein is administered to an individual orally. In some embodiments, an ASBTI described herein is delivered and/or released in the distal ileum of a human.

[00593] In various embodiments, contacting the distal ileum of an individual with an ASBTI (e.g., any ASBTI described herein) inhibits bile acid reuptake and increases the concentration of bile acids/salts near L-cells in the distal ileum and/or colon and/or rectum, thereby reducing intraenterocyte bile acid levels, reducing serum and/or liver bile acid levels, reducing total serum bile acid load, and/or reducing damage to ileal structure caused by cholestasis or cholestatic liver disease. Without being limited by any particular theory, reducing serum and/or liver bile acid levels improves hypercholeemia and/or cholestatic disease.

[00594] Administration of a compound described herein can be achieved by any suitable route, including, but not limited to, oral, intestinal, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Any compound or composition described herein can be administered in a manner or formulation suitable for treating a neonate or infant. Any compound or composition described herein can be administered as an oral formulation (e.g., solid or liquid) for treating a neonate or infant. Any compound or composition described herein can be administered prior to, with, or after a meal.

[00595] According to some embodiments, a compound or composition comprising a compound described herein is administered for prophylactic and/or therapeutic treatment. For therapeutic purposes, the compositions are administered to an individual already suffering from a disease or condition in an amount sufficient to cure or at least partially relieve the symptoms of the disease or condition. In various cases, amounts effective for this use depend on the severity and progression of the disease or condition, previous therapy, the individual's health status, weight and response to drugs, as well as the judgment of the treating physician.

[00596] For prophylactic purposes, compounds or compositions containing the compounds described herein can be administered to an individual predisposed to, or otherwise at risk for, a particular disease, disorder, or condition. In some embodiments of this use, the precise amounts of the compound administered depend on the individual's health status, weight, etc. Additionally, in some instances where a compound or composition described herein is administered to an individual, effective amounts for this use depend on the severity and progression of the disease, disorder, or condition, prior therapy, the individual's health status and response to medications, and the judgment of the treating physician.

[00597] According to some embodiments of the methods of the present invention, wherein the individual's condition does not improve after administration of a selected dose of a compound or composition described herein, at the discretion of the physician, the administration of the compound or composition described herein is optionally carried out chronically, i.e., over an extended period of time, including throughout the individual's life, to improve or otherwise control or limit the symptoms of the individual's disorder, disease, or condition.

[00598] According to certain embodiments of the methods of the present invention, an effective amount of a given agent varies depending on one or more factors, such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, and is determined in accordance with the particular circumstances characterizing the case, including, for example, the particular agent administered, the route of administration, the condition being treated, and the subject or host being treated. According to some embodiments, the doses administered include doses up to the maximum tolerated. According to some embodiments, the doses administered include doses up to the maximum tolerated for a neonate or infant.

[00599] In various embodiments of the methods of the present invention, the desired dose is typically presented as a single dose or divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, such as two, three, four or more sub-doses per day. In various embodiments, a single dose of ASBTI is administered every 6 hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours, every 96 hours, every 5 days, every 6 days, or once per week. In some embodiments, the total single dose of ASBTI is within the range described below.

[00600] According to various embodiments of the methods of the present invention, when the patient's condition does improve, the ASBTI is optionally administered continuously at the discretion of the physician; alternatively, the dose of the administered drug is temporarily reduced or temporarily suspended for a certain period of time (e.g., a "drug holiday"). The duration of the drug holiday can range from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. A dose reduction during a drug holiday includes from 10% to 100% of the original dose, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the original dose. In some embodiments, the total single dose of the ASBTI is within the range described below.

[00601] After the patient's condition improves, a maintenance dose is administered as needed. Thereafter, the dosage or frequency of administration, or both, is reduced depending on the symptoms to a level at which the improved disease, disorder, or condition is maintained. In some embodiments, patients require intermittent therapy on a long-term basis whenever symptoms recur.

[00602] In some cases, there are a large number of variables with respect to the individual treatment regimen, and significant deviations from these recommended values are contemplated within the scope described herein. The dosages described herein will not necessarily vary depending on a number of variables such as, by way of non-limiting example, the activity of the compound used, the disease or condition being treated, the route of administration, the needs of the individual subject, the severity of the disease or condition being treated, the judgment of the treating physician.

[00603] The toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD ₅₀ (the dose lethal to 50% of the population) and the ED ₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, and can be expressed as the ratio between the LD ₅₀ and the ED ₅₀ . Compounds with high therapeutic indices are preferred. In certain embodiments, data obtained from cell culture assays and animal studies are used to determine a dosage range for use in humans. In specific embodiments, the dosage of the compounds described herein is within a range of circulating concentrations that includes the ED ₅₀ with minimal toxicity. The dosage optionally varies within this range depending on the dosage form used and the route of administration used.

[00604] According to certain embodiments, the composition used or administered comprises an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a humectant.

[00605] According to some embodiments of the methods of the present invention, a composition used to prepare an oral dosage form or administered orally comprises an absorption inhibitor, an orally acceptable carrier, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional spreading agent, and an optional humectant. According to some embodiments, the orally administered compositions elicit an anorectal response. In particular embodiments, the anorectal response is an increase in the secretion of one or more enteroendocrines by cells of the colon and/or rectum (e.g., in L cells of the epithelial layer of the colon, ileum, rectum, or a combination thereof). According to some embodiments, the anorectal response is maintained for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. According to other embodiments, the anorectal response is maintained for a period of 24 hours to 48 hours, while in other embodiments, the anorectal response is maintained for a period of more than 48 hours.

Dosages

[00606] In various embodiments, the ASBTI is maralixibat or volixibat, or a pharmaceutically acceptable salt thereof.

[00607] In various embodiments, the efficacy and safety of administering an ASBTI to a patient is monitored by measuring serum 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, 7αC4 to sBA ratio (7αC4:sBA), serum conjugated bilirubin concentration, serum autotaxin concentration, serum bilirubin concentration, serum total cholesterol concentration, serum LDL-C concentration, serum ALT concentration, serum AST concentration, or a combination thereof. In various embodiments, the efficacy of administering an ASBTI is measured by monitoring observer-reported pruritus score (ITCHRO(OBS)), HRQoL score (e.g., PedsQL), CSS score, xanthoma score, height Z-score, weight Z-score, or various combinations thereof. In various embodiments, the method comprises monitoring serum 7α-hydroxy-4-cholesten-3-one (7αC4) levels, sBA concentrations, 7αC4 to sBA ratios (7αC4:sBA), serum conjugated bilirubin concentrations, serum total cholesterol concentrations, serum LDL-C concentrations, serum autotaxin concentrations, serum bilirubin concentrations, serum ALT concentrations, serum AST concentrations, or combinations thereof. In various embodiments, the method comprises monitoring observer-reported pruritus score (ITCHRO(OBS)), weight Z-score, HRQoL score (e.g., PedsQL), xanthoma score, CSS score, growth Z-score, or various combinations thereof.

[00608] In some embodiments, the ASBTI is administered at a dose of about or at least about 0.5 μg/kg, 1 μg/kg, 2 μg/kg, 3 μg/kg, 4 μg/kg, 5 μg/kg, 6 μg/kg, 7 μg/kg, 8 μg/kg, 9 μg/kg, 10 μg/kg, 15 μg/kg, 20 μg/kg, 25 μg/kg, 30 μg/kg, 35 μg/kg, 40 μg/kg, 45 μg/kg, 50 μg/kg, 55 μg/kg, 60 μg/kg, 65 μg/kg, 70 μg/kg, 75 μg/kg, 80 μg/kg, 85 mcg/kg, 90 mcg/kg, 100 mcg/kg, 140 mcg/kg, 150 mcg/kg, 200 mcg/kg, 240 mcg/kg, 280 mcg/kg, 300 mcg/kg, 250 mcg/kg, 280 mcg/kg, 300 mcg/kg, 400 mcg/kg, 500 mcg/kg , 560 mcg/kg, 600 mcg/kg, 700 mcg/kg, 800 mcg/kg, 900 mcg/kg, 1000 mcg/kg, 1100 mcg/kg, 1200 mcg/kg, 1300 mcg/kg, 1400 mcg/kg, 1500 mcg/kg, 1600 mcg/kg, 1700 mcg/kg, 1800 mcg/kg, 1900 mcg/kg or 2000 mcg/kg. In various embodiments, the ASBTI is administered at a dose of no more than about 1 mcg/kg, 2 mcg/kg, 3 mcg/kg, 4 mcg/kg, 5 mcg/kg, 6 mcg/kg, 7 mcg/kg, 8 mcg/kg, 9 mcg/kg, 10 mcg/kg, 15 mcg/kg, 20 mcg/kg, 25 mcg/kg, 30 mcg/kg, 35 mcg/kg, 40 mcg/kg, 45 mcg/kg, 50 mcg/kg, 55 mcg/kg, 60 mcg/kg, 65 mcg/kg, 70 mcg/kg, 75 mcg/kg, 80 mcg/kg, 85 mcg/kg, 90 mcg/kg, 100 mcg/kg, 140 mcg/kg, 150 mcg/kg, 200 mcg/kg, 240 mcg/kg, 300 mcg/kg, 250 mcg/kg, 280 mcg/kg, 300 mcg/kg, 400 mcg/kg, 500 mcg/kg, 560 mcg/kg, 600 mcg/ kg, 700 mcg/kg, 800 mcg/kg, 900 mcg/kg, 1000 mcg/kg, 1100 mcg/kg, 1200 mcg/kg, 1300 mcg/kg, 1400 mcg/kg, 1500 mcg/kg, 1600 mcg/kg, 1700 mcg/kg, 1800 mcg/kg, 1900 mcg/kg, 2000 or 2100 mcg/kg. In various embodiments, the ASBTI is administered at a dose of about or at least about 0.5 mg/day, 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9 mg/day, 10 mg/day, 11 mg/day, 12 mg/day, 13 mg/day, 14 mg/day, 15 mg/day, 16 mg/day, 17 mg/day, 18 mg/day, 19 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, 300 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day, 1000 mg/day. In various embodiments, the ASBTI is administered at a dose of no more than about 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7 mg/day, 8 mg/day, 9 mg/day, 10 mg/day, 11 mg/day, 12 mg/day, 13 mg/day, 14 mg/day, 15 mg/day, 16 mg/day, 17 mg/day, 18 mg/day, 19 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, 300 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day, 1000 mg/day, 1100 mg/day.

[00609] In some embodiments, the ASBTI is administered at a dose of from about 140 mcg/kg/day to about 1400 mcg/kg/day. In various embodiments, the ASBTI is administered at a dose of about or at least about 0.5 mcg/kg/day, 1 mcg/kg/day, 2 mcg/kg/day, 3 mcg/kg/day, 4 mcg/kg/day, 5 mcg/kg/day, 6 mcg/kg/day, 7 mcg/kg/day, 8 mcg/kg/day, 9 mcg/kg/day, 10 mcg/kg/day, 15 mcg/kg/day, 20 mcg/kg/day, 25 mcg/kg/day, 30 mcg/kg/day, 35 mcg/kg/day, 40 mcg/kg/day, 45 mcg/kg/day, 50 mcg/kg/day, 100 mcg/kg/day, 140 mcg/kg/day, 150 mcg/kg/day, 200 mcg/kg/day, 240 mcg/kg/day, 280 mcg/kg/day, 300 mcg/kg/day, 250 mcg/kg/day, 280 mcg/kg/day, 300 mcg/kg/day, 400 mcg/kg/day, 500 mcg/kg/day, 560 mcg/kg/day, 600 mcg/kg/day, 700 mcg/kg/day, 800 mcg/kg/day, 900 mcg/kg/day, 1000 mcg/kg/day, 1100 mcg/kg/day, 1200 mcg/kg/day or 1300 mcg/kg/day. In various embodiments, the ASBTI is administered at a dose no greater than about 1 mcg/kg/day, 2 mcg/kg/day, 3 mcg/kg/day, 4 mcg/kg/day, 5 mcg/kg/day, 6 mcg/kg/day, 7 mcg/kg/day, 8 mcg/kg/day, 9 mcg/kg/day, 10 mcg/kg/day, 15 mcg/kg/day, 20 mcg/kg/day, 25 mcg/kg/day, 30 mcg/kg/day, 35 mcg/kg/day, 40 mcg/kg/day, 45 mcg/kg/day, 50 mcg/kg/day, 100 mcg/kg/day, 140 mcg/kg/day, 150 mcg/kg/day, 200 mcg/kg/day, 240 mcg/kg/day, 280 mcg/kg/day, 300 mcg/kg/day, 250 mcg/kg/day, 280 mcg/kg/day, 300 mcg/kg/day, 400 mcg/kg/day, 500 mcg/kg/day, 560 mcg/kg/day, 600 mcg/kg/day, 700 mcg/kg/day, 800 mcg/kg/day, 900 mcg/kg/day, 1000 mcg/kg/day, 1100 mcg/kg/day, 1200 mcg/kg/day, 1300 mcg/kg/day or 1400 mcg/kg/day. In various embodiments, the ASBTI is administered at a dose of from about 0.5 mcg/kg/day to about 500 mcg/kg/day, from about 0.5 mcg/kg/day to about 250 mcg/kg/day, from about 1 mcg/kg/day to about 100 mcg/kg/day, from about 10 mcg/kg/day to about 50 mcg/kg/day, from about 10 mcg/kg/day to about 100 mcg/kg/day, from about 0.5 mcg/kg/day to about 2000 mcg/kg/day, from about 280 mcg/kg/day to about 1400 mcg/kg/day, from about 420 mcg/kg/day to about 1400 mcg/kg/day, from about 250 mcg/kg/day to about 550 mcg/kg/day, from about 560 mcg/kg/day to about 1400 mcg/kg/day, from about 700 mcg/kg/day to about 1400 mcg/kg/day, from about 560 mcg/kg/day to about 1200 mcg/kg/day, from about 700 mcg/kg/day to about 1200 mcg/kg/day, from about 560 mcg/kg/day to about 1000 mcg/kg/day, from about 700 mcg/kg/day to about 1000 mcg/kg/day, from about 800 mcg/kg/day to about 1000 mcg/kg/day, from about 200 mcg/kg/day to about 600 mcg/kg/day, from about 300 mcg/kg/day to about 600 mcg/kg/day, from about 400 mcg/kg/day to about 500 mcg/kg/day, from about 400 mcg/kg/day to about 600 mcg/kg/day, from about 400 mcg/kg/day to about 700 mcg/kg/day, from about 400 mcg/kg/day to about 800 mcg/kg/day, from about 500 mcg/kg/day to about 800 mcg/kg/day, from about 500 mcg/kg/day to about 900 mcg/kg/day, from about 600 mcg/kg/day to about 900 mcg/kg/day, from about 700 mcg/kg/day to about 900 mcg/kg/day, from about 200 mcg/kg/day to about 600 mcg/kg/day, from about 800 mcg/kg/day to about 900 mcg/kg/day, from about 100 mcg/kg/day to about 1500 mcg/kg/day, from about 300 mcg/kg/day to about 2000 mcg/kg/day, or from about 400 mcg/kg/day to about 2000 mcg/kg/day.

[00610] In some embodiments, the ASBTI is administered at a dose of from about 30 mcg/kg to about 1400 mcg/kg per dose. In some embodiments, the ASBTI is administered at a dose of from about 0.5 mcg/kg to about 2000 mcg/kg per dose, from about 0.5 mcg/kg to about 1500 mcg/kg per dose, from about 100 mcg/kg to about 700 mcg/kg per dose, from about 5 mcg/kg to about 100 mcg/kg per dose, from about 10 mcg/kg to about 500 mcg/kg per dose, from about 50 mcg/kg to about 1400 mcg/kg per dose, from about 300 mcg/kg to about 2000 mcg/kg per dose, from about 60 mcg/kg to about 1200 mcg/kg per dose, from about 70 mcg/kg to about 1000 mcg/kg per dose, from about 70 mcg/kg to about 700 mcg/kg per dose, from 80 mcg/kg to about 1000 mcg/kg per dose, from 80 mcg/kg to about 800 mcg/kg per dose, from 100 mcg/kg to about 800 mcg/kg per dose, from 100 mcg/kg to about 600 mcg/kg per dose, from 150 mcg/kg to about 700 mcg/kg per dose, from 150 mcg/kg to about 500 mcg/kg per dose, from 200 mcg/about 400 mcg/kg per dose, from 200 mcg/kg to about 300 mcg/kg per dose, or from 300 mcg/kg to about 400 mcg/kg per dose.

[00611] In some embodiments, the ASBTI is administered at a dose of from about 0.5 mg/day to about 550 mg/day. In various embodiments, the ASBTI is administered at a dose of from about 1 mg/day to about 500 mg/day, from about 1 mg/day to about 300 mg/day, from about 1 mg/day to about 200 mg/day, from about 2 mg/day to about 300 mg/day, from about 2 mg/day to about 200 mg/day, from about 4 mg/day to about 300 mg/day, from about 4 mg/day to about 200 mg/day, from about 4 mg/day to about 150 mg/day, from about 5 mg/day to about 150 mg/day, from about 5 mg/day to about 100 mg/day, from about 5 mg/day to about 80 mg/day, from about 5 mg/day to about 50 mg/day, from about 5 mg/day to about 40 mg/day, from about 5 mg/day to about 30 mg/day, from about 5 mg/day to about 20 mg/day, from about 5 mg/day to about 15 mg/day, from about 10 mg/day to about 100 mg/day, from about 10 mg/day to about 80 mg/day, from about 10 mg/day to about 50 mg/day, from about 10 mg/day to about 40 mg/day, from about 10 mg/day to about 20 mg/day, from about 20 mg/day to about 100 mg/day, from about 20 mg/day to about 80 mg/day, from about 20 mg/day to about 50 mg/day, or from about 20 mg/day to about 40 mg/day, or from about 20 mg/day to approximately 30 mg/day.

[00612] In some embodiments, the ASBTI is administered twice per day (BID) in an amount of about 200 mcg/kg to about 400 mcg/kg per dose. In some embodiments, the ASBTI is administered in an amount of about 280 mcg/kg/day to about 1400 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 400 mcg/kg/day to about 800 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 20 mg/day to about 50 mg/day. In some embodiments, the ASBTI is administered in an amount of about 5 mg/day to about 15 mg/day. In some embodiments, the ASBTI is administered in an amount of about 560 mcg/kg/day to about 1400 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 700 mcg/kg/day to about 1400 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 400 mcg/kg/day to about 800 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 700 mcg/kg/day to about 900 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 560 mcg/kg/day to about 1400 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of 700 mcg/kg/day to about 1400 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 200 mcg/kg/day to about 600 mcg/kg/day. In some embodiments, the ASBTI is administered in an amount of about 400 mcg/kg/day to about 600 mcg/kg/day.

[00613] In various embodiments, the ASBTI dose is a first dose value. In various embodiments, the ASBTI dose is a second dose value. In some embodiments, the second dose value is greater than the first dose value. In some embodiments, the second dose value is about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times greater than the first dose value. According to some embodiments, the second dose amount is no more than about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 times greater than the first dose amount.

[00614] In various embodiments, the ASBTI is administered once daily (QD) at one of the above-described doses or within one of the above-described dose ranges. In various embodiments, the ASBTI is administered twice daily (BID) at one of the above-described doses or within one of the above-described dose ranges. In various embodiments, the ASBTI is dosed daily, every other day, twice weekly, or once weekly.

[00615] According to various embodiments, the ASBTI is administered regularly for about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, or 800 weeks. In various embodiments, the ASBTI is administered for no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 48, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, or 1000 weeks. In various embodiments, the ASBTI is administered regularly for about or at least about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In various embodiments, the ASBTI is administered regularly for a period of no more than about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 years.

Reduction in symptoms or changes in disease-related laboratory parameters in cholestatic liver disease

[00616] According to various embodiments of the aforementioned methods of the present invention, administration of an ASBTI results in a reduction in a symptom or a change in a disease-related laboratory value of cholestatic liver disease (i.e., an improvement in the patient's condition) that is maintained for about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years or 10 years. In various embodiments, the reduction in a symptom or change in a laboratory value related to the disease comprises a decrease in sBA concentration, an increase in serum 7αC4 concentration, an increase in the 7αC4:sBA ratio, an increase in fBA excretion, a decrease in pruritus, a decrease in serum total cholesterol concentration, a decrease in serum LDL-C cholesterol concentration, a decrease in ALT levels, an increase in a quality of life score, an increase in a fatigue-related quality of life score, a decrease in xanthoma score, a decrease in serum autotaxin concentration, an increase in height, or a combination thereof. In various embodiments, the reduction in a symptom or a change in a laboratory value related to the disease is determined relative to a baseline. That is, a reduction in a symptom or a change in a disease-related laboratory value is determined relative to a measurement of the symptom or a change in a disease-related laboratory value prior to 1) a change in the dose of ASBTI administered to the patient, 2) a change in the dosing regimen that the patient is following, 3) the initiation of administration of the ASBTI, or 4) any other various changes made to reduce the symptom or change the disease-related laboratory value in the patient. In various embodiments, a reduction in a symptom or a change in a disease-related laboratory value is a statistically significant reduction.

[00617] According to various embodiments, the improvement in a symptom or change in a disease-related laboratory value of a cholestatic liver disease is measured as a progressive improvement in a symptom or change in a disease-related laboratory value over about or over at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years, or 10 years.

[00618] In some embodiments, the patient is a pediatric patient, and the reduction in symptoms or change in laboratory parameters related to the disease includes an increase or improvement in height. In some embodiments, the increase in height is measured relative to a baseline. In various embodiments, the increase in height is measured as an increase in a height Z-score or a weight Z-score. In various embodiments, the increase in a height Z-score or a weight Z-score is statistically significant. According to various embodiments, the height Z-score, the weight Z-score, or both increase by at least 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.7, 0.8, or 0.9 relative to baseline. According to some embodiments, the height Z-score, the weight Z-score, or both scores progressively increase during ASBTI administration for about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 48, 50, 60, 70, or 72 weeks.

[00619] In various embodiments, administration of the ASBTI results in an increase in the serum concentration of 7αC4. In various embodiments, the serum concentration of 7αC4 increases by about or at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 times relative to baseline. According to various embodiments, the serum 7αC4 concentration increases by about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or 10000% relative to baseline.

[00620] According to various embodiments, administration of an ASBTI results in an increase in the 7αC4:sBA ratio by about or at least about 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1000, 2000, 3000, 4000, 5000, or 10,000 times relative to baseline.

[00621] In various embodiments, administration of an ASBTI results in an increase in fBA excretion. In some embodiments, administration of an ASBTI results in an increase in fBA excretion by about or at least about 100%, 110%, 115%, 120%, 130%, 150%, 200%, 250%, 275%, 300%, 400%, 500%, 600%, 700%, 800%, 1000%, 5000%, 10000%, or 15000% relative to baseline. In various embodiments, the excretion of fBA is increased by about or at least about 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times the baseline. In some embodiments, the excretion of fBA is increased by about or at least about 100 μmol, 150 μmol, 200 μmol, 250 μmol, 300 μmol, 400 μmol, 500 μmol, 600 μmol, 700 μmol, 800 μmol, 900 μmol, 1000 μmol, or 1500 μmol relative to the baseline. In various embodiments, administration of the ASBTI results in a dose-dependent increase in fBA excretion, such that administration of a higher dose of the ASBTI results in a correspondingly higher level of fBA excretion. In various embodiments, the ASBTI is administered at a dose sufficient to result in an increase in bile acid secretion relative to baseline by at least about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times baseline.

[00622] According to various embodiments, administration of the ASBTI results in a decrease in sBA concentration by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 31%, 35%, 40%, 45%, 50%, 55%, 57%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% relative to baseline.

[00623] In some embodiments, administration of an ASBTI results in a decrease in the severity of pruritus. In various embodiments, the severity of pruritus is measured using an ITCHRO(OBS) score, an ITCHRO score, a CSS score, or a combination thereof. In various embodiments, administration of an ASBTI results in a decrease in the ITCHRO(OBS) score on a scale of 1 to 4 by about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3 relative to baseline. In various embodiments, administration of the ASBTI results in a decrease in the ITCHRO score on a scale of 1 to 10 by about or at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10. In various embodiments, administration of the ASBTI results in a decrease in the ITCHRO(OBS) score, the ITCHRO score, or both to zero. In various embodiments, administration of the ASBTI results in a decrease in the ITCHRO(OBS) score or the ITCHRO score to 1.0 or less. In various embodiments, administering the ASBTI results in a decrease in the CSS by approximately 0.1, 0.2, 0.3, 0.4, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.25, 2.5, or 3 relative to the baseline. In various embodiments, administering the ASBTI results in a decrease in the CSS to zero. In various embodiments, administration of the ASBTI results in a decrease in the CSS score, ITCHRO(OBS) score, ITCHRO score, or a combination thereof by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline. According to various embodiments, the reduction in the CSS score, ITCHRO(OBS) score, ITCHRO score, or combination thereof from baseline is observed on 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of days.

[00624] In some embodiments, patients with a higher baseline ITCHRO(OBS) score exhibit a greater reduction in a symptom or change in a disease-related laboratory value than patients with a lower baseline ITCHRO(OBS) score. In some embodiments, patients with a baseline ITCHRO(OBS) score of at least 2, 3, or 4 or an ITCHRO score of at least 4, 5, 6, 7, 8, 9, or 10 exhibit a greater reduction in a symptom or change in a disease-related laboratory value from baseline than the lower reduction in patients with a lower baseline pruritus severity. In various embodiments, patients who have a PSC and a baseline ITCHRO score of at least 4 exhibit a greater reduction in a symptom or change in a disease-related laboratory value than patients who have a baseline ITCHRO score of less than 4. In various embodiments, the method includes predicting that a patient will have a greater reduction in a symptom or change in a disease-related laboratory value if the patient's baseline ITCHRO score is at least 4 compared to a patient who has a baseline ITCHRO score of less than 4. In various embodiments, the smaller reduction is about or less than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the larger reduction. In various embodiments, the difference in symptom reduction or change in disease-related laboratory value (i.e., between a greater and lesser reduction) between patients having an ITCHRO score of at least 4 at baseline and patients having an ITCHRO score of less than 4 at baseline is measured at about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 6 months, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 23 months, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, 5.5 years, 6 years, 6.5 years, 7 years, 8 years, 9 years or 10 years after the first ASBTI administration in the first or second dose.

[00625] In various embodiments, the reduction in the severity of pruritus caused by administration of an ASBTI to a patient positively correlates with a reduction in the concentration of sBA in the patient. In various embodiments, a greater reduction in the concentration of sBA in the patient correlates with a corresponding greater reduction in the severity of pruritus.

[00626] In various embodiments, administration of the ASBTI results in a decrease in serum LDL-C concentration compared to a baseline. In some embodiments, the serum LDL-C concentration is decreased by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% compared to a baseline.

[00627] In some embodiments, administration of an ASBTI results in a decrease in total serum cholesterol compared to a baseline. In some embodiments, administration of an ASBTI results in a decrease in serum LDL-C compared to a baseline. In some embodiments, total serum cholesterol, serum LDL-C, or both are decreased by about or at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% relative to a baseline. In various embodiments, administration of the ASBTI results in a decrease in serum total cholesterol, serum LDL-C, or both by about or at least about 1 mg/dL, 2 mg/dL, 3 mg/dL, 4 mg/dL, 5 mg/dL, 10 mg/dL, 12.5 mg/dL, 15 mg/dL, 20 mg/dL, 30 mg/dL, 40 mg/dL, or 50 mg/dL relative to baseline.

[00628] In various embodiments, administration of an ASBTI results in a decrease in the serum concentration of autotaxin. In some embodiments, administration of an ASBTI results in a decrease in the concentration of autotaxin by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% relative to baseline.

[00629] In various embodiments, administration of the ASBTI results in an increase in a quality of life score or a fatigue-related quality of life questionnaire score. The quality of life questionnaire score may be a health-related quality of life (HRQoL) score. In some embodiments, the HRQoL score is a PedsQL score. In various embodiments, administration of the ASBTI results in an increase in the PedsQL score or the fatigue-related PedsQL score by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45%, or 50% relative to baseline.

[00630] In various embodiments, administration of the ASBTI results in a decrease in xanthoma score compared to a baseline. In some embodiments, the xanthoma score is reduced by about or at least about 2.5%, 5%, 10%, 15%, 20%, 35%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to a baseline.

[00631] According to various embodiments, administration of an ASBTI results in a reduction in a symptom or a change in a laboratory value related to a disease for about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks or 1 year.

[00632] According to various embodiments, the serum bilirubin concentration is at a baseline level prior to administration or at a normal level at about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks or 1 year.

[00633] In various embodiments, the serum ALT concentration is at baseline prior to administration or at a normal level at about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or 1 year. In some embodiments, administration of the ASBTI results in a decrease in ALT relative to baseline of about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%.

[00634] In various embodiments, the serum ALT concentration, the serum AST concentration, the serum bilirubin concentration, the serum conjugated bilirubin concentration, or various combinations thereof are within the normal range or at baseline prior to administration at about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks or 1 year. In various embodiments, administration of the ASBTI does not result in a statistically significant change from baseline in serum bilirubin concentration, serum AST concentration, serum ALT concentration, serum alkaline phosphatase concentration, or some combination thereof over a period of at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 4 months, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks or 1 year.

Introducing ASBTI to Increase Growth

[00635] In various embodiments, administration of an ASBTI results in an increase in height or weight at about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 week, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks or 1 year or approximately that period.

[00636] According to some embodiments, the increase in height is maintained at a constant dose of ASBTI for about or for at least about, or for up to about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 2 years, 3 years, 4 years or 5 years.

[00637] According to some embodiments, the weight or height Z-score continues to increase for about or for at least about, or for up to about, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 2 years, 3 years, 4 years or 5 years.

[00638] According to various embodiments, the method comprises administering to the patient an ASBTI in a first dose amount. According to some embodiments, the method further comprises administering the ASBTI in a second dose amount greater than the first dose amount after first administering the ASBTI in a first dose amount over a period of time. According to various embodiments, the period of time is about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 55 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 96 weeks, 100 weeks, 2 years, 110 weeks, 120 weeks, 130 weeks, 140 weeks, 143 weeks, 150 weeks, 3 years, 155 weeks, 160 weeks, 167 weeks, 170 weeks, 179 weeks, 180 weeks, 190 weeks, 191 weeks, 200 weeks, 4 years or 5 years.

[00639] According to some embodiments, the weight or height Z-score increases in a dose-dependent manner in response to administration of the ASBTI, such that a second dose results in a greater increase in weight or height Z-score. In some embodiments, if the first dose does not result in an increase in height or weight Z-score by about or at least about 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.7, 0.8, or 0.9 relative to baseline, then the patient is administered a second dose such that the second dose actually results in an increase in height or weight Z-score of about or at least about 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.7, 0.8, or 0.9 relative to the baseline.

[00640] In various embodiments, administration of the first dose or the second dose BID at an unchanged total daily dose results in a greater increase in growth than administration of the same total daily dose QD level.

[00641] In various embodiments, the second dose is a total daily dose administered by BID. In various embodiments, the second dose results in an increase in height compared to a baseline measured during administration of the first dose. In various embodiments, the second dose results in a greater increase in height compared to a baseline measured prior to administration of the ASBTI than the increase in height compared to a baseline caused by administration of the first dose. According to various embodiments, administration of the second dose results in an increase in the Z-score by about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to the baseline height Z-score measured during administration of the first dose to the patient. According to various embodiments, administration of the second dose results in an increase in the Z-score compared to the baseline measured before administration of the ASBTI that is at least about or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% greater than the increase in the Z-score compared to the baseline measured before administration of the ASBTI caused by administration of the ASBTI in the first dose.

Genotype PFIC 2

[00642] In various embodiments, the BSEP deficiency is progressive familial intrahepatic cholestasis (PFIC 2), benign recurrent intrahepatic cholestasis, or intrahepatic cholestasis of pregnancy. In various embodiments, the patient has residual BSEP function. In various embodiments, the patient has at least about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%%, 25%, 20%, 25%, 20%, 5%, 2.5%, or 1% BSEP function relative to a healthy individual without cholestatic liver disease. According to various embodiments, the patient has a maximum of about 99%, 95%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 25%, 20%, 5%, 2.5% of BSEP function relative to a healthy individual without cholestatic liver disease. BSEP deficiency can lead to impaired or decreased bile flow or cholestasis.

[00643] In various embodiments, the BSEP deficiency is caused by a mutation in the ABCB11 gene. In various embodiments, the mutation in the ABCB11 gene is a non-truncating mutation. Typically, truncating mutations of the ABCB11 gene result in no residual function of the encoded BSEP (a "severe" mutation). In various embodiments, the ABCB11 gene comprises a mutation and does not comprise any truncating mutations. The mutation in the ABCB11 gene may be a missense or nonsense mutation, an insertion, or a deletion. In embodiments, the ABCB11 gene comprises the E297G or D482G mutation, or both, alternatively referred to as "mild" mutations or "mild PFIC 2." In some embodiments, the ABCB 11 gene comprises a missense mutation and does not comprise an E297G or D482G missense mutation, alternatively referred to as "intermediate" mutations or "intermediate form of PFIC 2." The ABCB 11 gene may comprise E297G, D482G, alternative missense mutations, insertions, deletions, and various combinations thereof. In various embodiments, the alternative missense mutation may be selected from one of those mutations listed in Byrne, et al., "Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messanger RNA Splicing," Hepatology, 49:553-567 (2009)), which is incorporated herein by reference in its entirety for all purposes.

[00644] In various embodiments, the patient has a complete loss of BSEP activity. In various embodiments, the patient with a complete loss of BSEP activity is homozygous for ABCB11 genes that have mutations that result in a complete loss of the encoded BSEP activity (e.g., truncating or frameshift mutations). In various embodiments, the patient has residual BSEP activity. In various embodiments, the patient having residual BSEP activity is heterozygous for an ABCB11 gene that has mutations that result in a complete loss of the encoded BSEP activity (e.g., patients having an ABCB11 gene with a truncating mutation and a wild-type ABCB11 gene, or patients having an ABCB11 gene with a truncating mutation and an ABCB11 gene that has mutations encoding BSEP that have residual activity, but activity that is reduced compared to wild-type BSEP). In certain embodiments, the person having residual BSEP activity is homozygous for ABCB11 genes having mutations that result in residual BSEP activity and reduced BSEP activity compared to the wild type (e.g., patients having ABCB11 genes with the same or different missense mutations). In some embodiments, the patient having residual BSEP activity is heterozygous for ABCB11 genes having mutations that result in residual BSEP activity and reduced BSEP activity compared to the wild type (e.g., patients having a wild type ABCB11 gene and an ABCB11 gene with a missense mutation).

[00645] According to various embodiments, the method involves determining the genotype of the patient. Determining the genotype may include any of various methods known in the art for determining a gene sequence for a patient, including, but not limited to, identification of a genomic DNA restriction fragment length polymorphism, random amplified polymorphic detection of genomic DNA, detection of an amplified fragment length polymorphism, polymerase chain reaction, DNA sequencing, allele-specific oligonucleotide probes, hybridization to DNA microarrays or beads, and various combinations thereof. According to various embodiments, determining the genotype includes determining the sequence of the ABCB11 gene.

[00646] In some embodiments, determining the genotype comprises identifying and characterizing a mutation in the ABCB11 gene. Determining the genotype may comprise determining the sequence of a portion or all of the ABCB11 gene. Determining the genotype may further comprise determining the sequence of a genomic region surrounding the ABCB11 gene or determining the sequence of one or more introns and/or exons of the ABCB11 gene. Determining the genotype may comprise characterizing the ABCB11 gene by identifying one, more, or all mutations of the alleles encoding the ABCB11 gene in the patient. In various embodiments, determining the genotype comprises determining whether the ABCB11 gene has a truncating mutation, an insertion, a deletion, a missense mutation, an E197G mutation, a D482G mutation, or various combinations thereof.

Dose modulation

[00647] According to various embodiments, the method includes changing the dosage of ASBTI administered to the patient. Modulating includes determining the 7αC4:sBA ratio for the patient at a baseline (e.g., before administration of the ASBTI or before modulating (e.g., increasing) the dosage of the ASBTI) and further determining the 7αC4:sBA ratio after administration of the ASBTI in a first dose or modulating (e.g., increasing) the dosage amount of the ASBTI to a second dose. If the 7αC4:sBA ratio does not increase by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1000, 2000, 3000, 4000, 5000, or 10,000 times compared to baseline, the ASBTI dose is increased until the ratio increases by at least about 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1000, 2000, 3000, 4000, 5000, or 10,000 times the baseline. According to various embodiments, the ASBTI dose is increased or decreased to achieve and maintain a certain 7αC4:sBA ratio.

[00648] According to various embodiments, the modulation comprises increasing the dose of the ASBTI from a first dose amount to a second dose amount greater than the first dose amount if the 7αC4:sBA ratio initially increases by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1,000, 2,000, 3,000, 4,000, 5,000, or 10,000 times the baseline and then begins to decrease or decreases to values less than 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1000, 2000, 3000, 4000, 5000, or 10,000 times or more compared to baseline. The dose is increased until the 7αC4:sBA ratio increases to at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1000, 2000, 3000, 4000, 5000, or 10,000 times the baseline.

[00649] According to some embodiments, modulating involves administering a first dose of an ASBTI to the patient. If the 7αC4:sBA ratio does not increase or increases by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1000, 2000, 3000, 4000, 5000, or 10,000 times the baseline, the patient is then administered a second dose of the ASBTI that is greater than the first dose. The dose administered to the patient continues to increase until the 7αC4:sBA ratio increases by at least 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 150, 200, 300, 500, 750, 1000, 2000, 3000, 4000, 5000, or 10,000 times the baseline.

[00650] According to various embodiments, the 7αC4:sBA ratio is measured approximately daily, biweekly, weekly, bimonthly, monthly, every two months, every three months, every four months, every five months, every six months, or annually, and the ASBTI dose is modulated as needed each time the ratio is measured.

Pharmaceutical compositions

[00651] In some embodiments, the ASBTI is administered as a pharmaceutical composition comprising the ASBTI (the composition or the pharmaceutical composition). Any composition described herein can be formulated for delivery to the ileum, rectum, and/or colon. In more specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and/or colon. It should be understood that, as used herein, delivery to the colon includes delivery to the sigmoid colon, the transverse colon, and/or the ascending colon. In still more specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and/or colon, administered rectally. In other specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and/or colon, administered orally.

[00652] Provided herein, in certain embodiments, is a pharmaceutical composition comprising a therapeutically effective amount of any compound described herein. In some cases, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTI described herein).

[00653] According to certain embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including, for example, excipients and auxiliaries that facilitate processing of the active compounds into preparations suitable for pharmaceutical use. According to certain embodiments, the proper formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Mareel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), all references to which are incorporated herein in their entirety for all purposes.

[00654] As used herein, a pharmaceutical composition refers to a mixture of a compound described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and/or excipients. In some cases, the pharmaceutical composition facilitates administration of the compound to an individual or to a cell. In certain embodiments of the methods of treatment or use provided herein, therapeutically effective amounts of the compounds described herein are administered in a pharmaceutical composition to an individual suffering from a disease, disorder, or condition to be treated. In particular embodiments, the individual is a human. As discussed herein, the compounds described herein are used either alone or in combination with one or more additional therapeutic agents.

[00655] According to certain embodiments, the pharmaceutical compositions described herein are administered to an individual by any route, including one or more of a variety of routes of administration, such as, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration.

[00656] In certain embodiments, the pharmaceutical compositions described herein include one or more compounds described herein as an active ingredient in the form of a free acid or a free base, or in the form of a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are used as an N-oxide or in a crystalline or amorphous form (i.e., a polymorph). In some situations, a compound described herein exists as tautomers. All tautomers are included within the scope of the compounds provided herein. In certain embodiments, a compound described herein exists in unsolvated or solvated form, wherein solvated forms include any pharmaceutically acceptable solvent, such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be described herein.

[00657] "Carrier" includes, in some embodiments, a pharmaceutically acceptable excipient and is selected based on compatibility with the compounds described herein, such as compounds of any of Formula I-VI, and the release profile properties of the desired dosage form. Examples of carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Mareel Decker, New York, N.Y., 1980 and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), all references of which are incorporated herein in their entirety for all purposes.

[00658] Additionally, in some embodiments, the pharmaceutical compositions described herein are formulated as a dosage form. Thus, in some embodiments, provided herein is a dosage form comprising a compound described herein suitable for administration to an individual. In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00659] According to some embodiments, provided herein is a composition comprising an enteroendocrine peptide secretagogue and, optionally, a pharmaceutically acceptable carrier for alleviating symptoms of cholestasis or cholestatic liver disease in an individual.

[00660] In certain embodiments, the composition comprises an enteroendocrine peptide secretagogue and an absorption inhibitor. In particular embodiments, the absorption inhibitor is an inhibitor that inhibits the absorption of (or at least one of) a specific enteroendocrine peptide secretagogue with which it is combined. In some embodiments, the composition comprises an enteroendocrine peptide secretagogue, an absorption inhibitor, and a carrier (e.g., an orally acceptable carrier or a rectal acceptable carrier, depending on the route of intended administration). In certain embodiments, the composition comprises an enteroendocrine peptide secretagogue, an absorption inhibitor, a carrier, and one or more of a cholesterol absorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor, a spreading agent, and a humectant.

[00661] In other embodiments, the compositions described herein are administered orally for non-systemic delivery of the ASBTI to the rectum and/or colon, including the sigmoid colon, transverse colon, and/or ascending colon. In particular embodiments, compositions formulated for oral administration are, by way of non-limiting example, enteric-coated dosage forms or formulated oral dosage forms, such as tablets and/or capsules.

Absorption inhibitors

[00662] According to certain embodiments, a composition described herein as formulated for extrasystemic delivery of an ASBTI further comprises an absorption inhibitor. As used herein, an absorption inhibitor includes an agent or group of agents that inhibit bile acid/salt absorption.

[00663] Suitable bile acid absorption inhibitors (also described herein as absorption inhibiting agents) may include, but are not limited to, anion exchange matrices, polyamines, quaternary amine-containing polymers, quaternary ammonium salts, polyallylamine polymers and copolymers, colesevelam, colesevelam hydrochloride, cholestagel (N,N,N-trimethyl-6-(2-propenylamino)-1-hexaneaminium chloride polymer with (chloromethyl)oxirane, 2-propen-1-amine, and N-2-propenyl-1-decanamine hydrochloride), cyclodextrins, chitosan, chitosan derivatives, bile acid-binding carbohydrates, bile acid-binding lipids, bile acid-binding proteins and proteinaceous substances, and bile acid-binding antibodies and albumins. Suitable cyclodextrins include those that bind bile acids/salts, such as, but not limited to, β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Suitable proteins include those that bind bile acids/salts, such as, but not limited to, bovine serum albumin, egg albumin, casein, α-acid glycoprotein, gelatin, soy proteins, peanut proteins, almond proteins, and wheat vegetable proteins.

[00664] In certain embodiments, the absorption inhibitor is cholestyramine. In particular embodiments, cholestyramine is combined with a bile acid. Cholestyramine, an ion exchange resin, is a styrene polymer containing quaternary ammonium groups crosslinked with divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In particular embodiments, colestipol is combined with a bile acid. Colestipol, an ion exchange resin, is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane.

[00665] In certain embodiments of the compositions and methods described herein, the ASBTI is linked to an absorption inhibitor, while in other embodiments, the ASBTI and the absorption inhibitor are separate molecular entities.

Cholesterol absorption inhibitors

[00666] In some embodiments, the composition described herein optionally includes at least one cholesterol absorption inhibitor. Suitable cholesterol absorption inhibitors include, but are not limited to, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors, stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholine analogs, β-lactam cholesterol absorption inhibitors, sulfate polysaccharides, neinsomycin, plant saponins, plant sterols, the phytostanol preparation FM-VP4, sitostanol, β-sitosterol, acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors, avasimibe, implitapide, steroidal glycosides, and the like. Suitable analogs of encetimibe include, but are not limited to, SCH 48461, SCH 58053, and the like. Suitable ACT inhibitors include, but are not limited to, trimethoxy fatty acid anilides such as Cl-976, 3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide, melinamide, and the like. β-Lactam cholesterol absorption inhibitors include, but are not limited to, βR-(4S)-1,4-bis-(4-methoxyphenyl)-3-β-phenylpropyl)-2-azetidinone, and the like.

Peptidase inhibitors

[00667] In some embodiments, the compositions described herein optionally include at least one peptidase inhibitor. Such peptidase inhibitors include, but are not limited to, dipeptidyl peptidase-4 (DPP-4) inhibitors, neutral endopeptidase inhibitors, and enzyme converting inhibitors. Suitable dipeptidyl peptidase-4 (DPP-4) inhibitors include, but are not limited to, vildagliptin, 2.S)-1-{2-[β-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile, sitagliptin, βR)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, saxagliptin, and (1S,3S,5S)-2-[(2S)-2-amino-2-β-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile. Such neutral endopeptidase inhibitors include, but are not limited to, candoxatrilate and ecadotril.

Spreading enhancers/wetting agents

[00668] In certain embodiments, the composition described herein optionally comprises a spreading agent. In some embodiments, the spreading agent is used to improve distribution of the composition in the colon and/or rectum. Suitable spreading agents include, but are not limited to, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, colloidal silicon dioxide, propylene glycol, cyclodextrins, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethyl glycerides, polycarbophil, di-n-octyl ethers, Cetiol™ OE, polyalkylene glycol fatty alcohol ethers, Aethoxal™ B), 2-ethylhexyl palmitate, Cegesoft™ C 24) and isopropyl fatty acid esters.

[00669] In some embodiments, the compositions described herein optionally comprise a wetting agent. In some embodiments, the wetting agent is used to improve the wettability of the composition in the colon and rectum. Suitable wetting agents include, but are not limited to, surfactants. In some embodiments, the surfactants are selected from, but are not limited to, polysorbate (e.g., 20 or 80), stearyl hetanoate, caprylic/capric fatty acid esters of _C12 - _C18 saturated fatty alcohols, isostearyl diglycerol isostearic acid, sodium dodecyl sulfate, isopropyl myristate, isopropyl palmitate, and an isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture.

Vitamins

[00670] According to some embodiments, the methods provided herein further comprise administering one or more vitamins.

[00671] According to some embodiments, the vitamin is vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.

[00672] According to some embodiments, the vitamin is a fat-soluble vitamin, such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherols, phylloquinone. According to a preferred embodiment, the fat-soluble vitamin is tocopherol polyethyleneglycol succinate (TPGS).

Bile acid sequestrants/binders

[00673] In some embodiments, the labile bile acid sequestrant is an enzyme-dependent bile acid sequestrant. In some embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentration in the human colon or rectum compared to the concentration found in the small intestine. Examples of activated microflora systems include dosage forms comprising pectin, galactomannan and/or azohydrogels and/or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylopyranoside, or the like) of an active agent. Examples of gastrointestinal microflora enzymes include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[00674] In certain embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant. In some embodiments, the labile bile acid sequestrant releases bile acid or degrades after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds of sequestration. In some embodiments, the labile bile acid sequestrant releases bile acid or degrades after 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds of sequestration. In some embodiments, the labile bile acid sequestrant releases bile acid or degrades after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes of sequestration. In some embodiments, the labile bile acid sequestrant releases bile acid or degrades after about 15, 20, 25, 30, 35, 45, 50, or 55 minutes of sequestration. In some embodiments, the labile bile acid sequestrant releases bile acid or degrades after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours of sequestration. In some embodiments, the labile bile acid sequestrant releases bile acid or degrades after 1, 2, or 3 days of sequestration.

[00675] In some embodiments, the labile bile acid sequestrant has a low affinity for a bile acid. In some embodiments, the labile bile acid sequestrant has a high affinity for a primary bile acid and a low affinity for a secondary bile acid.

[00676] In some embodiments, the labile bile acid sequestrant is a pH-dependent bile acid sequestrant. In certain embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 6 or below and a low affinity for a bile acid at a pH greater than 6. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 6.5 or below and a low affinity for a bile acid at a pH greater than 6.5. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7 or below and a low affinity for a bile acid at a pH above 7. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.1 or below and a low affinity for a bile acid at a pH above 7.1. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.2 or below and a low affinity for a bile acid at a pH above 7.2. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.3 or below and a low affinity for a bile acid at a pH above 7.3. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.4 or below and a low affinity for a bile acid at a pH above 7.4. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.5 or below and a low affinity for a bile acid at a pH above 7.5. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.6 or below and a low affinity for a bile acid at a pH above 7.6. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.7 or below and a low affinity for a bile acid at a pH above 7.7. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 7.8 or below and a low affinity for a bile acid at a pH above 7.8. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 6. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 6.5. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.1. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.2. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.3. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.4. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH greater than 7.5. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH greater than 7.6. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH greater than 7.7. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH greater than 7.8. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH greater than 7.9.

[00677] In certain embodiments, the labile bile acid sequestrant is a lignin or modified lignin. In some embodiments, the labile bile acid sequestrant is a polycationic polymer or copolymer. In certain embodiments, the labile bile acid sequestrant is a polymer or copolymer comprising one or more N-alkenyl-N-alkylamine residues; one or more N,N,N-trialkyl-N-(N'-alkenylamino)alkylazane residues; one or more N,N,N-trialkyl-N-alkenylazane residues; one or more alkenylamine residues; or a combination thereof. In some embodiments, the bile acid binder is cholestyramine and various compositions including cholestyramine are described in, for example, U.S. Patent Nos. 3,383,281; 3,308,020; 3,769,399; 3,846,541; 3,974,272; 4,172,120; 4,252,790; 4,340,585; 4,814,354; 4,874,744; 4,895,723; 5,695,749; and 6,066,336, all of which are incorporated herein by reference in their entireties for all purposes. In some embodiments, the bile acid binder is colestipol or cholesevelam.

Routes of administration, dosage forms and dosage regimens

[00678] In some embodiments, the compositions described herein and the compositions administered by the methods described herein are formulated to inhibit bile acid reuptake or reduce serum or hepatic bile acid levels. In some embodiments, the compositions described herein are formulated for rectal or oral administration. In some embodiments, such formulations are administered rectally or orally, respectively. In some embodiments, the compositions described herein are combined with a device for topical delivery of the compositions to the rectum and/or colon (sigmoid colon, transverse colon, or ascending colon). In some embodiments, for rectal administration, the composition described herein is provided as an enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jellies, or retention enemas. In some embodiments for oral administration, the compositions described herein are formulated for oral administration and enteric delivery to the colon.

[00679] In certain embodiments, the compositions or methods described herein are non-systemic. In some embodiments, the compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum, rather than systemically (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not absorbed systemically). In some embodiments, the oral compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum, rather than systemically (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not absorbed systemically). In some embodiments, the rectal compositions described herein deliver the ASBTI to the distal ileum, colon, and/or rectum, rather than systemically (e.g., a substantial portion of the enteroendocrine peptide secretagogue is not absorbed systemically). In certain embodiments, the non-systemic compositions described herein systemically deliver less than 90% by weight of the ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 80% by weight of the ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 70% by weight of the ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 60% by weight of the ASBT1. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 50% by weight of the ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 40% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 30% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 25% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 20% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 15% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 10% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 5% by weight of ASBTI. In some embodiments, systemic absorption is determined by any suitable method, including the total amount in the bloodstream, the amount excreted after administration, etc.

[00680] In certain embodiments, the compositions and/or formulations described herein are administered at least once per day. In certain embodiments, the ASBTI-containing formulations are administered at least twice per day, while in other embodiments, the ASBTI-containing formulations are administered at least three times per day. In certain embodiments, the ASBTI-containing formulations are administered up to five times per day. It should be understood that in certain embodiments, the dosing regimen for the ASBTI-containing composition described herein is determined based on various factors, such as the age, gender, and diet of the patient.

[00681] The concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 1 M. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 750 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 5 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 10 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 25 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 50 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 100 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the formulations described herein ranges from about 200 mM to about 500 mM.

[00682] According to certain embodiments, by targeting the distal gastrointestinal tract (e.g., the distal ileum, colon, and/or rectum), the compositions and methods described herein provide efficacy (e.g., in reducing microbial growth and/or alleviating symptoms of cholestasis or cholestatic liver disease) with a reduced dose of an enteroendocrine peptide secretagogue (e.g., compared to an oral dose that does not target the distal gastrointestinal tract).

Compositions for rectal administration

[00683] The pharmaceutical compositions described herein for non-systemic delivery of a compound described herein to the rectum and/or colon are formulated for rectal administration as rectal enemas, rectal foams, rectal gels, and rectal suppositories. The components of such formulations are described herein. It should be understood that, as used herein, the pharmaceutical compositions and compositions are or comprise the formulations described herein. In some embodiments, the rectal formulations include rectal enemas, foams, gels, or suppositories.

[00684] According to certain embodiments, liquid excipients or carrier cosolvents in the compositions and/or formulations described herein include, but are not limited to, purified water, propylene glycol, PEG200, PEG300, PEG400, PEG600, polyethylene glycol, ethanol, 1-propanol, 2-propanol, 1-propen-3-ol (allyl alcohol), propylene glycol, glycerin, 2-methyl-2-propanol, formamide, methylformamide, dimethylformamide, ethylformamide, diethylformamide, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethylurea, 1,3-dimethyl-2-imidazolidinone, propylene carbonate, 1,2-butylene carbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethyl sulfoxide, hexamethylphosphoramide, dimethyl pyruvic acetal, dimethyl isosorbide and combinations thereof.

[00685] According to some embodiments, stabilizers used in the compositions and/or formulations described herein include, but are not limited to, partial glycerides of polyoxyethylene saturated fatty acids.

[00686] According to certain embodiments, surfactants/emulsifiers used in the compositions and/or formulations described herein include, by way of non-limiting example, mixtures of cetostearyl alcohol with sorbitan, esterified polyoxyethylene fatty acids, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid esters, fatty acids, sulfated fatty acids, phosphated fatty acids, sulfosuccinates, amphoteric surfactants, nonionic poloxamers, nonionic meroxapoles, petroleum derivatives, aliphatic amines, polysiloxane derivatives, sorbitan fatty acid esters, laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbate 60, sorbitan monostearate, their pharmaceutically acceptable salts and combinations thereof.

[00687] In some embodiments, nonionic surfactants used in the compositions and/or formulations described herein include, but are not limited to, phospholipids, alkyl poly(ethylene oxide), poloxamers (e.g., poloxamer 188), polysorbates, sodium dioctyl sulfosuccinate, Brij™-30 (laureth-4), Brij™-58 (ceteth-20) and Brij™-78 (steareth-20), Brij™-721 (steareth-21), Crillet-1 (polysorbate 20), Crillet-2 (polysorbate 40), Crillet-3 (polysorbate 60), Crillet 45 (polysorbate 80), Myrj-52 (PEG-40 stearate), Myrj-53 (stearate PEG-50), Pluronic™F77 (poloxamer 217), Pluronic™F87 (poloxamer 237), Pluronic™F98 (poloxamer 288), Pluronic™L62 (poloxamer 182), Pluronic™L64 (poloxamer 184), Pluronic™F68 (poloxamer 188), Pluronic™L81 (poloxamer 231), Pluronic™L92 (poloxamer 282), Pluronic™L101 (poloxamer 331), Pluronic™P103 (poloxamer 333), Pluracare™ F 108 NF (poloxamer 338) and Pluracare™ F 127 NF (poloxamer 407) and combinations thereof. Pluronic™ polymers are commercially available from BASF, USA and Germany.

[00688] According to some embodiments, anionic surfactants used in the compositions and/or formulations described herein include, but are not limited to, sodium lauryl sulfate, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, alkyl sulfate salts, alkyl benzene sulfonate, and combinations thereof.

[00689] According to some embodiments, cationic surfactants used in the compositions and/or formulations described herein include, but are not limited to, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, other alkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylated tallow, and combinations thereof.

[00690] According to certain embodiments, thickening agents used in the compositions and/or formulations described herein include, but are not limited to, natural polysaccharides, semi-synthetic polymers, synthetic polymers, and combinations thereof. Natural polysaccharides include, but are not limited to, gum arabic, agar, alginates, carrageenan, guar, acacia, tragacanth, pectins, dextran, gellan, and xanthan gums. Semi-synthetic polymers include, but are not limited to, cellulose esters, modified starches, modified celluloses, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Synthetic polymers include, but are not limited to, polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyacrylates, carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones), polyvinyl acetate, polyethylene glycols, and poloxamer. Other thickeners include, but are not limited to, polyoxyethylene glycol isostearate, cetyl alcohol, polyglycol 300 isostearate, propylene glycol, collagen, gelatin, and fatty acids (e.g., lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, oleic acid, etc.).

[00691] According to some embodiments, chelating agents used in the compositions and/or formulations described herein include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or its salts, phosphates, and combinations thereof.

[00692] In some embodiments, the concentration of the chelating agent or agents used in the rectal formulations described herein is a suitable concentration, such as about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w/v).

[00693] According to some embodiments, preservatives used in the compositions and/or formulations described herein include, but are not limited to, parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben, methylparaben, butylparaben, propylparaben, monothioglycerin, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid, sulfur dioxide, maleic acid, propyl gallate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorobutanol, phenoxyethanol, cetylpyridinium chloride, phenylmercuric nitrate, thimerosal and combinations thereof.

[00694] According to certain embodiments, antioxidants used in the compositions and/or formulations described herein include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, oxygen, quinones, tert-butylhydroquinone, erythorbic acid, olive (olea eurpaea) oil, pentasodium penetrate, pentetic acid, tocopheryl, tocopheryl acetate, and combinations thereof.

[00695] According to some embodiments, the concentration of the antioxidant or antioxidants used in the rectal formulations described herein is sufficient to achieve the desired result, such as about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w/v).

[00696] Lubricants used in the compositions and/or formulations described herein include, but are not limited to, a natural or synthetic fat or oil (e.g., tris-fatty acid glycerate, etc.). In some embodiments, lubricants include, but are not limited to, glycerin (also referred to as glycerol, glycerol, 1,2,3-propanetriol, and trihydroxypropane), polyethylene glycols (PEG), polypropylene glycol, polyisobutene, polyethylene oxide, behenic acid, behenyl alcohol, sorbitol, mannitol, lactose, polydimethylsiloxane, and combinations thereof.

[00697] According to certain embodiments, mucoadhesive and/or bioadhesive polymers are used in the compositions and/or formulations described herein as agents for inhibiting the absorption of an enteroendocrine peptide secretagogue through the rectal or colonic mucosa. Bioadhesive or mucoadhesive polymers include, but are not limited to, hydroxypropyl cellulose, polyethylene oxide homopolymers, polyvinyl ether maleic acid copolymers, methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polycarbophil, polyvinylpyrrolidone, carbopol, polyurethanes, polyethylene oxide and polypropylene oxide copolymers, sodium carboxymethyl cellulose, polyethylene, polypropylene, lectins, xanthan gum, alginates, sodium alginate, polyacrylic acid, chitosan, hyaluronic acid and their ester derivatives, vinyl acetate homopolymer, calcium polycarbophil, gelatin, natural gums, karaya, tragacanth, algin, chitosan, staccharides, pectins and their combinations.

[00698] In some embodiments, the pH buffers/adjusters used in the compositions and/or formulations described herein include, but are not limited to, phosphoric acid, sodium or potassium phosphate monobasic, triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, sodium acetate monobasic, acetic acid, acetate, citric acid, sodium citrate anhydrous, sodium citrate dihydrate, and combinations thereof. In certain embodiments, an acid or base is added to adjust the pH. Suitable acids or bases include, but are not limited to, HCl, NaOH, and KOH.

[00699] According to certain embodiments, the concentration of the buffering agent or agents used in the rectal formulations described herein is sufficient to achieve or maintain a physiologically desired pH, such as about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (weight/weight).

[00700] Tonicity modifiers used in the compositions and/or formulations described herein include, but are not limited to, sodium chloride, potassium chloride, sodium phosphate, mannitol, sorbitol, or glucose.

Oral administration for delivery to the colon

[00701] In certain aspects, a composition or formulation comprising one or more compounds described herein is administered orally for local delivery of an ASBTI or a compound described herein to the colon and/or rectum. Unit dosage forms of such compositions include a pill, tablet, or capsule formulated for enteric delivery to the colon. In certain embodiments, such pills, tablets, or capsules comprise the compositions described herein contained in or embedded in microspheres. In some embodiments, the microspheres include, but are not limited to, chitosan microporous HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, the oral dosage forms are prepared using conventional methods known to those skilled in the pharmaceutical art. For example, in certain embodiments, the tablets are manufactured using standard tablet processing procedures and equipment. An exemplary method for forming tablets is direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives or the like. In alternative embodiments, tablets are prepared using wet granulation or dry granulation processes. In some embodiments, tablets are formed rather than compressed, starting from a wet or pliable material.

[00702] According to certain embodiments, tablets prepared for oral administration contain various excipients, including, but not limited to, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavors, and the like. In some embodiments, binders are used to impart cohesive qualities to the tablet to ensure that the tablet remains intact after compression. Suitable binders include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums such as sodium alginate gum, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, etc.), veegum, and combinations thereof. In certain embodiments, diluents are used to increase the volume of the tablet so that a practical tablet size is obtained. Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry sugar, powdered sugar, and combinations thereof. According to certain embodiments, lubricants are used to facilitate the production of tablets; examples of suitable lubricants include, but are not limited to, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter, glycerin, magnesium stearate, calcium stearate, stearic acid and combinations thereof. According to some embodiments, disintegrants are used to facilitate disintegration of the tablet and include, but are not limited to, starches, clays, celluloses, algins, gums, crosslinked polymers and combinations thereof. Fillers include, but are not limited to, materials such as silicon dioxide, titanium dioxide, aluminum oxide, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. According to certain embodiments, stabilizers are used to inhibit or slow down drug degradation reactions, which include, for example, oxidative reactions. According to certain embodiments, surfactants are anionic, cationic, amphoteric or nonionic surfactants.

[00703] In some embodiments, the ASBTI or other compounds described herein are administered orally in combination with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., the distal ileum, colon, and/or rectum).

[00704] In certain embodiments, a composition described herein comprises ASBTI or other compounds described herein in combination with a matrix (e.g., a hypermellose-containing matrix) that provides controlled release of the active agent in the distal ileum and/or rectum. In some embodiments, the composition comprises a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) and provides controlled release of the active agent in the distal ileum. Examples of such pH sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic polymers (e.g., anionic polymers of methacrylic acid and/or methacrylic acid esters, such as Carbopol® polymers) that contain acidic groups (e.g., -COOH, _-SO3H ) and swell to the alkaline pH of the intestine (e.g., pH from about 7 to about 8). In some embodiments, a composition suitable for controlled release in the distal ileum comprises a microparticulate active agent (e.g., a micronized active agent). In some embodiments, a non-enzymatically degradable lactic acid-glycolic acid copolymer (PLGA) core is suitable for delivering an enteroendocrine peptide secretagogue to the distal ileum. According to some embodiments, the dosage form comprising the enteroendocrine peptide secretagogue is coated with an enteric polymer (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic polymers of methacrylic acid or esters of methacrylic acid, or the like) for delivery to the distal ileum and/or the colon. According to some embodiments, bacterially activated systems are suitable for targeted delivery to the distal ileum. Examples of activated microflora systems include dosage forms comprising pectin, galactomannan, and/or azohydrogels and/or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylopyranoside, or the like) of the active agent. Examples of gastrointestinal microflora enzymes include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[00705] The pharmaceutical composition described herein optionally comprises an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoam, antioxidant, preservative, or one or more combinations thereof. In some aspects, using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th edition (2000), a film coating is provided around the compound of Formula I composition. In one embodiment, the compound described herein is in the form of a particle and some or all of the particles of the compound are coated. In some embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and do not contain a coating.

[00706] According to additional embodiments, a tablet or capsule comprising ASBTI or other compounds described herein is characterized by having a film coating for delivery to target sites in the gastrointestinal tract. Examples of enteric film coatings include, but are not limited to, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethyleneglycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, and the like.

Dosage forms and compositions for pediatric patients

[00707] Provided herein, in some embodiments, is a dosage form or composition for pediatric patients comprising a therapeutically effective amount of any compound described herein. In some cases, the pharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTI described herein).

[00708] According to some embodiments, suitable dosage forms for the dosage form or composition for pediatric patients include, as a non-limiting example, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, suspensions, solutions, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummy candies, orally disintegrating tablets, powders for dissolution as a suspension or solution, powdered oral powders or granules, dragees, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. According to some embodiments, the present document provides a pharmaceutical composition, wherein the dosage form for pediatric patients is selected from a solution, syrup, suspension, elixir, powder for dissolution as a suspension or solution, dispersible/effervescent tablet, chewable tablet, chewable candy, lollipop, freezer lozenge, pastille, orally disintegrating strip, orally disintegrating tablet, orally disintegrating strip, sachet, and powder or granule of openable capsules for oral use.

[00709] According to another aspect, provided herein is a pharmaceutical composition wherein at least one excipient is a flavoring or sweetening agent. In some embodiments, provided herein is a coating. In some embodiments, provided herein is a taste-masking technology selected from coating drug particles with a neutral-tasting polymer by spray drying, wet granulation, fluidized bed, and microencapsulation; coating with molten paraffin from a mixture of molten waxes and other pharmaceutical adjuvants; entrapping drug particles by complexation, flocculation, or coagulation of an aqueous polymer dispersion; adsorption of drug particles onto resinous and inorganic carriers; and a solid dispersion in which the drug and one or more neutral-tasting compounds are melted and cooled or co-precipitated by solvent evaporation. According to some embodiments, provided herein is a delayed or sustained release formulation comprising drug particles or granules in a rate controlling polymer or matrix.

[00710] Suitable sweeteners include sucrose, glucose, fructose, or intense sweeteners, i.e., agents with a high sweetening capacity compared to sucrose (e.g., at least 10 times sweeter than sucrose). Suitable intense sweeteners include aspartame, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate, neomate, neohesperidin dihydrochalcone or mixtures thereof, thaumatin, palatinit, stevioside, rebaudioside, magnasweet®. The total concentration of sweeteners can range from virtually zero to about 300 mg/mL based on the liquid composition after dissolution.

[00711] To enhance the palatability of the liquid composition when dissolved in an aqueous medium, one or more taste imparting substances may be added to the composition to mask the taste of the ASBT inhibitor. The taste masking agent may be a sweetener, a flavoring agent, or a combination thereof. Taste masking agents typically comprise from about 0.1% to 5% by weight of the total pharmaceutical composition. According to a preferred embodiment of the present invention, the composition contains both a sweetener(s) and a flavoring agent(s).

[00712] A flavoring agent as used herein is a substance capable of enhancing the taste or aroma of a composition. Suitable natural or synthetic flavoring agents can be selected from standard reference books, such as Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of flavorings and/or sweeteners used in the compositions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berries, blackcurrant, toffee, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cold cherry, cold citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, spearmint, neohesperidin DC, neotame, orange, pear, peach, peppermint, mint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, mint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, silitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, pear, xylitol, or any combination of these flavor ingredients such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof. Flavors can be used individually or in combination of two or more. According to some embodiments, the aqueous liquid dispersion comprises a sweetener or flavoring agent in a concentration of from about 0.001% to about 5.0% by volume of the aqueous dispersion. According to one embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent in a concentration of from about 0.001% to about 1.0% by volume of the aqueous dispersion. According to another embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent in a concentration of from about 0.005% to about 0.5% by volume of the aqueous dispersion. According to yet another embodiment, the aqueous liquid dispersion comprises a sweetener or flavoring agent in a concentration of from about 0.01% to about 1.0% by volume of the aqueous dispersion. According to another embodiment, the aqueous liquid dispersion contains a sweetener or flavoring agent in a concentration of from about 0.01% to about 0.5% by volume of the aqueous dispersion.

[00713] In certain embodiments, a pharmaceutical composition for pediatric patients described herein includes one or more compounds described herein as an active ingredient in the form of a free acid or free base or in the form of a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are used as an N-oxide or in a crystalline or amorphous form (i.e., a polymorph). In some situations, a compound described herein exists as tautomers. All tautomers are included within the scope of the compounds provided herein. In some embodiments, a compound described herein exists in unsolvated or solvated form, wherein solvated forms include any pharmaceutically acceptable solvent, such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be described herein.

[00714] A "carrier" for pharmaceutical compositions for pediatric patients includes, in some embodiments, a pharmaceutically acceptable excipient and is selected based on compatibility with the compounds described herein, such as compounds of any of Formula I-VI, and the release profile properties of the desired dosage form. Examples of carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980 and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), all references of which are incorporated herein by reference in their entirety for all purposes.

[00715] Additionally, in some embodiments, the pharmaceutical compositions described herein for pediatric patients are formulated as a dosage form. Thus, in some embodiments, provided herein is a dosage form comprising a compound described herein suitable for administration to an individual. In certain embodiments, suitable dosage forms include, by way of non-limiting example, aqueous oral dispersions, liquids, gels, syrups, elixirs, suspensions, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00716] In certain aspects, a composition or formulation for pediatric patients comprising one or more compounds described herein is administered orally for local delivery of the ASBTI or a compound described herein to the colon and/or rectum. Unit dosage forms of such compositions include a pill, tablet, or capsule formulated for enteric delivery to the colon. In some embodiments, such pills, tablets, or capsules comprise the compositions described herein contained in or embedded in microspheres. In some embodiments, the microspheres include, but are not limited to, chitosan microporous HPMC capsules and cellulose acetate butyrate (CAB) microspheres. In some embodiments, the oral dosage forms are prepared using conventional methods known to those skilled in the pharmaceutical art. For example, in some embodiments, the tablets are manufactured using standard tablet processing procedures and equipment. An exemplary method for forming tablets is direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives or the like. In alternative embodiments, tablets are prepared using wet granulation or dry granulation processes. In some embodiments, tablets are formed rather than compressed, starting from a wet or pliable material.

[00717] According to some embodiments, tablets prepared for oral administration contain various excipients, including, but not limited to, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavors, and the like. According to some embodiments, binders are used to impart cohesive properties to the tablet to ensure that the tablet remains intact after compression. Suitable binders include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums such as sodium alginate gum, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, etc.), veegum, and combinations thereof. In certain embodiments, diluents are used to increase the volume of the tablet so that a practical tablet size is obtained. Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, and combinations thereof. According to certain embodiments, lubricants are used to facilitate the production of tablets; examples of suitable lubricants include, but are not limited to, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. According to some embodiments, disintegrants are used to facilitate disintegration of the tablet and include, but are not limited to, starches, clays, celluloses, algins, gums, crosslinked polymers, and combinations thereof. Fillers include, but are not limited to, materials such as silicon dioxide, titanium dioxide, aluminum oxide, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. According to some embodiments, stabilizers are used to inhibit or slow down drug degradation reactions, which include, for example, oxidative reactions. According to some embodiments, surfactants are anionic, cationic, amphoteric or nonionic surfactants.

[00718] In some embodiments, the ASBTI or other compounds described herein are administered orally in combination with a carrier suitable for delivery to the distal gastrointestinal tract (e.g., the distal ileum, colon, and/or rectum).

[00719] In certain embodiments, a composition for pediatric patients described herein comprises ASBTI or other compounds described herein in combination with a matrix (e.g., a matrix comprising hypermellose) that provides controlled release of the active agent in the distal ileum and/or colon. In some embodiments, the composition comprises a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) and provides controlled release of the active agent in the distal ileum. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic polymers (e.g., anionic polymers of methacrylic acid and/or methacrylic acid esters, such as Carbopol® polymers) that contain acidic groups (e.g., -COOH, _-SO3H ) and swell at the alkaline pH of the intestine (e.g., pH from about 7 to about 8). In some embodiments, a composition suitable for controlled release in the distal ileum comprises an active agent in the form of microparticles (e.g., a micronized active agent). In some embodiments, a non-enzymatically degradable poly(lactic-co-glycolic acid) copolymer (PLGA) core is suitable for delivering an enteroendocrine peptide secretagogue to the distal ileum. In some embodiments, the dosage form comprising the enteroendocrine peptide secretagogue is coated with an enteric polymer (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic methacrylic acid polymers or methacrylic acid esters, for example) for delivery to the distal ileum and/or colon. In some embodiments, the bacterially activated systems are suitable for targeted delivery to the distal ileum. Examples of activated microflora systems include dosage forms containing pectin, galactomannan and/or azohydrogels and/or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylopyranoside, etc.) of the active agent. Examples of gastrointestinal microflora enzymes include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[00720] The pharmaceutical composition for pediatric patients described herein optionally comprises an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoam, antioxidant, preservative, or one or more combinations thereof. In some aspects, using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th edition (2000), a film coating is provided around the compound of Formula I composition. In one embodiment, the compound described herein is in the form of a particle and some or all of the particles of the compound comprise a coating. In some embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and do not contain a coating.

[00721] According to additional embodiments, a tablet or capsule comprising ASBTI or other compounds described herein comprises a film coating for delivery to target sites in the gastrointestinal tract. Examples of enteric film coatings include, but are not limited to, hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethyleneglycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, and the like.

Solid dosage forms for administration to pediatric patients

[00722] Solid dosage forms for administration to pediatric patients according to the present invention can be manufactured by standard manufacturing methods. Non-limiting examples of oral solid dosage forms for administration to pediatric patients are described below.

Effervescent compositions

[00723] The effervescent compositions of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[00724] Effervescent compositions comprise an effervescent pair of a basic component and an acidic component, wherein the components react in the presence of water to form a gas. According to some embodiments, the basic component may comprise, for example, a carbonate or bicarbonate of an alkali or alkaline earth metal. The acidic component may include, for example, an aliphatic carboxylic acid or a salt thereof, such as citric acid. Each of the basic and acidic components may independently comprise, for example, from 25% to 55% (by weight) of the effervescent composition. The ratio of the acidic component to the basic component may be in the range of from 1:2 to 2:1.

[00725] The effervescent compositions of the present invention may be formulated using additional pharmaceutically acceptable carriers or excipients, if desired. For example, one or more taste-masking agents may be used. Coloring agents may also be used, since pediatric patients often prefer colorful pharmaceutical combinations. The compositions may be in the form of, for example, tablets, granules or powders, granules or powders presented in sachets. Chewable tablets

[00726] The chewable tablets of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[00727] Chewable tablets are tablets that are designed to disintegrate in the mouth through the action of chewing or sucking, and as a result, the active ingredient has a greater opportunity to come into contact with the bitter taste receptors on the tongue.

[00728] One way to overcome this problem is to absorb the active ingredient onto a suitable substrate. This approach is known in the art and is described, for example, in U.S. Patent No. 4,647,459, which is incorporated herein by reference in its entirety for all purposes.

[00729] Another approach involves forming the active ingredient into an aggregate together with a pre-swollen, substantially anhydrous hydrocolloid. The hydrocolloid absorbs saliva and acquires a slippery texture that allows lubrication of the aggregate particles and masks the taste of the active ingredient. This approach is known in the art and is described, for example, in European Patent Application 0 190 826, which is incorporated herein by reference in its entirety for all purposes.

[00730] Another approach involves the use of a water-insoluble hygroscopic excipient such as microcrystalline cellulose. This approach is known in the art and is described, for example, in U.S. Patent No. 5,275,823, which is incorporated herein by reference in its entirety for all purposes.

[00731] In addition to the above approaches, the chewable tablets of the present invention may also contain other standard tabletting excipients such as a disintegrant and a taste masking agent.

Orodispersible tablets

[00732] The orodispersible tablets of the present invention can be prepared according to techniques well known in the art of pharmacy.

[00733] In the orodispersible tablets of the present invention, the mixtures of excipients are such that they provide such a disintegration rate that its disintegration in the oral cavity occurs in an extremely short time and especially in a period of less than sixty seconds. According to some embodiments, the mixture of excipients is characterized in that the active substance is in the form of microcrystals of microgranules with or without a coating. According to some embodiments, the orodispersible tablet contains one or more disintegrants such as carboxymethylcellulose or insoluble cross-linked PVP, one or more swelling agents that may include carboxymethylcellulose, starch, modified starch or microcrystalline cellulose, or, optionally, direct compression sugar.

Powders for dissolution

[00734] The powder for dissolution of the pharmaceutical compositions of the present invention can be prepared according to technologies well known in the field of pharmacy.

[00735] According to some embodiments, the powder for dissolving the compositions of the present invention comprises an effective amount of at least one internal dehydrating agent. The internal dehydrating agent can improve the stability of the powder. According to some embodiments, the internal dehydrating agent is magnesium citrate or disodium carbonate. According to some embodiments, the powder composition comprises pharmaceutically acceptable diluents such as sucrose, dextrose, mannitol, xylitol, or lactose.

[00736] The powder compositions of the present invention may be placed in sachets or vials for simultaneous dissolution or for short-term storage in liquid form (e.g., 7 days).

Jelly Bean

[00737] The chewable candies of the present invention can be prepared according to techniques well known in the pharmaceutical art.

[00738] Traditional chewy candies are made on the basis of gelatin. Gelatin gives the candies elasticity, a desirable chewy consistency and a longer shelf life. According to some embodiments, the pharmaceutical composition of the chewy candies of the present invention includes a binder, a sweetener and an active ingredient.

[00739] In some embodiments, the binder is pectin gel, gelatin, food starch, or any combination thereof.

[00740] According to some embodiments, the chewy candy comprises sweeteners, a binder, natural and/or artificial flavors, colors, and preservatives. According to some embodiments, the chewy candy comprises glucose syrup, natural cane juice, gelatin, citric acid, lactic acid, natural colors, natural flavors, fractionated coconut oil, and carnauba wax.

Liquid dosage forms

[00741] The pharmaceutical liquid dosage forms of the present invention can be prepared according to techniques well known in the field of pharmacy.

[00742] A solution refers to a liquid pharmaceutical composition in which the active ingredient is dissolved in a liquid. Pharmaceutical solutions of the present invention include syrups and elixirs. A suspension refers to a liquid pharmaceutical composition in which the active ingredient is in the form of a precipitate in a liquid.

[00743] It is desirable to have a specific pH value and/or maintain it within a specific pH range in a liquid dosage form. In order to control the pH, a suitable buffer system can be used. In addition, the buffer system should have sufficient capacity to maintain the desired pH range. Examples of the buffer system used in the present invention include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art. Preferably, the buffer system includes sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, etc. The concentration of the buffer system in the final suspension varies depending on factors such as the strength of the buffer system and the pH/pH ranges required for the liquid dosage form. According to one embodiment, the concentration is in the range of 0.005 to 0.5% w/v in the final liquid dosage form.

[00744] The pharmaceutical composition comprising the liquid dosage form of the present invention may also contain a suspending/stabilizing agent to prevent sedimentation of the active material. Over time, sedimentation may result in caking of the active substance on the inner walls of the product packaging, resulting in difficulties with redispersion and accurate dosing. Suitable stabilizing agents include, but are not limited to, polysaccharide stabilizers such as xanthan, guar and tragacanth gums, as well as cellulose derivatives HPMC (hydroxypropyl methylcellulose), methylcellulose and Avicel RC-591 (microcrystalline cellulose/sodium carboxymethylcellulose). In another embodiment, polyvinylpyrrolidone (PVP) may also be used as a stabilizing agent.

[00745] In addition to the above components, the ASBTI oral suspension form may also optionally contain other excipients typically found in pharmaceutical compositions, such as alternative solvents, taste masking agents, antioxidants, fillers, acidulants, enzyme inhibitors, and other components as described in Handbook of Pharmaceutical Excipients, Rowe et al., Eds., ^4th Edition, Pharmaceutical Press (2003), which is incorporated herein by reference in its entirety for all purposes.

[00746] The addition of an alternative solvent may help increase the solubility of the active ingredient in the liquid dosage form and, therefore, the absorption and bioavailability in the body of the subject. Preferably, alternative solvents include methanol, ethanol, or propylene glycol, etc.

[00747] According to another aspect, the present invention provides a method for preparing a liquid dosage form. The method comprises the steps of bringing ASBTI or its pharmaceutically acceptable salts into admixture with components including glycerin or syrup, or a mixture thereof, a preservative, a buffer system and a suspending/stabilizing agent, etc., in a liquid medium. Typically, the liquid dosage form is prepared by uniformly and thoroughly mixing these various components in a liquid medium. For example, components such as glycerin or syrup, or a mixture thereof, a preservative, a buffer system and a suspending/stabilizing agent, etc., can be dissolved in water to form an aqueous solution, then the active ingredient can be dispersed in the aqueous solution to form a suspension.

[00748] In some embodiments, the volume of the liquid dosage form provided herein can be from about 5 mL to about 50 mL. In some embodiments, the volume of the liquid dosage form provided herein can be from about 5 mL to about 40 mL. In some embodiments, the volume of the liquid dosage form provided herein can be from about 5 mL to about 30 mL. In some embodiments, the volume of the liquid dosage form provided herein can be from about 5 mL to about 20 mL. In some embodiments, the volume of the liquid dosage form provided herein can be from about 10 mL to about 30 mL. In some embodiments, the volume of the liquid dosage form provided herein can be about 20 mL. In some embodiments, the ASBTI can be from about 0.001% to about 90% of the total volume. In some embodiments, the ASBTI can be from about 0.01% to about 80% of the total volume. In some embodiments, the ASBTI may be from about 0.1% to about 70% of the total volume. In some embodiments, the ASBTI may be from about 1% to about 60% of the total volume. In some embodiments, the ASBTI may be from about 1% to about 50% of the total volume. In some embodiments, the ASBTI may be from about 1% to about 40% of the total volume. In some embodiments, the ASBTI may be from about 1% to about 30% of the total volume. In some embodiments, the ASBTI may be from about 1% to about 20% of the total volume. In some embodiments, the ASBTI may be from about 1% to about 10% of the total volume. In some embodiments, the ASBTI may be from about 5% to about 70% of the total volume. In some embodiments, the ASBTI may be from about 5% to about 60% of the total volume. In some embodiments, the ASBTI may be from about 5% to about 50% of the total volume. In some embodiments, the ASBTI may be from about 5% to about 40% of the total volume. In some embodiments, the ASBTI may be from about 5% to about 30% of the total volume. In some embodiments, the ASBTI may be from about 5% to about 20% of the total volume. In some embodiments, the ASBTI may be from about 5% to about 10% of the total volume. In some embodiments, the ASBTI may be from about 10% to about 50% of the total volume. In some embodiments, the ASBTI may be from about 10% to about 40% of the total volume. In some embodiments, the ASBTI may be from about 10% to about 30% of the total volume. In some embodiments, the ASBTI may be from about 10% to about 20% of the total volume. According to one embodiment, the resulting liquid dosage form may have a liquid volume of 10 ml to 30 ml, preferably 20 ml, and the active ingredient may be present in an amount of from about 0.001 mg/ml to about 16 mg/ml, or from about 0.025 mg/ml to about 8 mg/ml, or from about 0.1 mg/ml to about 4 mg/ml, or about 0.25 mg/ml, or about 0.5 mg/ml, or about 1 mg/ml, or about 2 mg/ml, or about 4 mg/ml, or about 5 mg/ml, or about 8 mg/ml, or about 10 mg/ml, or about 12 mg/ml, or about 14 mg/ml, or about 16 mg/ml. Bile acid sequestrant

[00749] In certain embodiments, an oral formulation for use in any method described herein is, for example, an ASBTI in combination with a labile bile acid sequestrant. A labile bile acid sequestrant is a bile acid sequestrant with a labile affinity for bile acids. In certain embodiments, a bile acid sequestrant described herein is an agent that sequesters (e.g., absorbs or soaks up) bile acid and/or its salts.

[00750] In particular embodiments, the labile bile acid sequestrant is an agent that binds (e.g., absorbs or soaks up) a bile acid and/or its salts and releases at least a portion of the absorbed or soaked bile acid and/or its salts in the distal gastrointestinal tract (e.g., the colon, ascending colon, sigmoid colon, distal colon, rectum, or any combination thereof). In certain embodiments, the labile bile acid sequestrant is an enzyme-dependent bile acid sequestrant. In particular embodiments, the enzyme is a bacterial enzyme. In some embodiments, the enzyme is a bacterial enzyme found in high concentrations in the human colon or rectum compared to the concentration found in the small intestine. Examples of activated microflora systems include dosage forms containing pectin, galactomannan and/or azohydrogels and/or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylopyranoside, or the like) of an active agent. Examples of gastrointestinal microflora enzymes include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, and the like. According to some embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant (i.e., the bile acid sequesters the bile acid and/or its salts and after a certain time releases at least a portion of the bile acid and/or its salts). In some embodiments, the time-dependent bile acid sequestrant is an agent that degrades over time in an aqueous environment. In some embodiments, the labile bile acid sequestrant described herein is a bile acid sequestrant that has a low affinity for bile acids and/or their salts, thereby allowing the bile acid sequestrant to continue to sequester bile acids and/or their salts in an environment where the bile acids/salts and/or their salts are present in a high concentration, and to release them in an environment where the bile acids/salts and/or their salts are present in a lower relative concentration. In some embodiments, the labile bile acid sequestrant has a high affinity for a primary bile acid and a low affinity for a secondary bile acid, which allows the bile acid sequestrant to sequester a primary bile acid or a salt thereof, followed by the release of a secondary bile acid or a salt thereof, since the primary bile acid or a salt thereof is converted (e.g., metabolized) into a secondary bile acid or a salt thereof. In some embodiments, the labile bile acid sequestrant is a pH-dependent bile acid sequestrant. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for a bile acid at a pH of 6 or below and a low affinity for a bile acid at a pH above 6. In certain embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 6.

[00751] In some embodiments, the labile bile acid sequestrants described herein include any compound, such as a macrostructured compound, that can sequester bile acids/salts and/or their salts by any suitable mechanism. For example, in certain embodiments, the bile acid sequestrants sequester bile acids/salts and/or their salts through ionic interactions, polar interactions, static interactions, hydrophobic interactions, lipophilic interactions, hydrophilic interactions, steric interactions, and the like. In certain embodiments, the macrostructured compounds sequester bile acids/salts and/or sequestrants by entrapping the bile acids/salts and/or their salts in pockets of the macrostructured compounds and, optionally, by other interactions such as those described above. In some embodiments, bile acid sequestrants (e.g., labile bile acid sequestrants) include, but are not limited to, lignin, modified lignin, polymers, polycationic polymers and copolymers, polymers and/or copolymers comprising any one or more of N-alkenyl-N-alkylamine residues; one or more of N,N,N-trialkyl-N-(N'-alkenylamino)alkylazane residues; one or more N,N,N-trialkyl-N-alkenylazane residues; one or more alkenylamine residues, or a combination thereof, or any combination thereof.

Covalent bond of a drug with a carrier

[00752] In some embodiments, strategies used to target the colon include, but are not limited to, covalently linking ASBTI or other compounds described herein to a carrier, coating the dosage form with a pH-sensitive polymer for delivery upon reaching the pH of the colonic environment, using redox-sensitive polymers, using a slow-release formulation, using coatings that are specifically degraded by colonic bacteria, using a bioadhesive system, and using osmotic-controlled drug delivery systems.

[00753] According to certain embodiments, such oral administration of a composition comprising ASBTI or other compounds described herein involves covalently linking to a carrier, wherein upon oral administration the linked moiety remains intact in the stomach and small intestine. Upon entering the colon, the covalent linkage is disrupted due to changes in pH, enzymes, and/or degradation by intestinal microflora. According to certain embodiments, the covalent linkage between ASBTI and the carrier includes, but is not limited to, azo bonds, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates, and amino acid conjugates (high hydrophilicity and long chain amino acid carrier).

Polymer coating: pH sensitive polymers

[00754] In some embodiments, the oral dosage forms described herein are coated with an enteric coating to facilitate delivery of the ASBTI or other compounds described herein to the colon and/or rectum. In certain embodiments, the enteric coating is one that remains intact in the low pH environment of the stomach, but dissolves readily when the optimal dissolution pH of the particular coating is reached, which depends on the chemical composition of the enteric coating. The thickness of the coating will depend on the solubility characteristics of the coating material. In certain embodiments, the thickness of the coating used in such formulations described herein is from about 25 μm to about 200 μm.

[00755] In certain embodiments, the compositions or formulations described herein are coated such that the ASBTI or other compounds described herein in the composition or formulation are delivered to the colon and/or rectum without being absorbed in the upper intestine. In a specific embodiment, specific delivery to the colon and/or rectum is achieved by coating the dosage form with polymers that degrade only in the colonic pH environment. In alternative embodiments, the composition is coated with an enteric coating that dissolves at intestinal pH and an outer layer matrix that slowly degrades in the intestine. In some such embodiments, the matrix slowly degrades until only the core composition containing the enteroendocrine peptide secretagogue (and, in some embodiments, the agent absorption inhibitor) remains and the core is delivered to the colon and/or rectum.

[00756] According to certain embodiments, pH-dependent systems

utilize a progressively increasing pH along the human gastrointestinal tract (GIT) from the stomach (pH 1-2, which increases to 4 during digestion), the small intestine (pH 6-7) at the digestion site, and to 7-8 at the distal ileum. According to certain embodiments, oral dosage forms of the compositions described herein are coated with a pH-sensitive polymer(s) to provide sustained release and protection of the enteroendocrine peptide secretagogues from gastric juice. According to certain embodiments, such polymers are capable of withstanding the lower pH of the stomach and proximal small intestine, but disintegrate at the neutral or slightly alkaline pH of the terminal ileum and/or ileocecal junction. Thus, according to certain embodiments, provided herein is an oral dosage form comprising a coating, wherein the coating comprises a pH-sensitive polymer. According to some embodiments, polymers used for targeting the colon and/or rectum include, as a non-limiting example, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers, Eudragit L100, Eudragit S100, Eudragit L-30D, Eudragit FS-30D, Eudragit L100-55, polyvinyl acetate phthalate, hydroxypropyl ethylcellulose phthalate, hydroxypropyl methylcellulose 50 phthalate, hydroxypropyl methylcellulose 55 phthalate, cellulose acetate trimelliate, cellulose acetate phthalate, and combinations thereof.

[00757] According to certain embodiments, oral dosage forms suitable for delivery to the colon and/or rectum comprise a coating that comprises a biodegradable and/or bacterially degradable polymer or polymers that are degraded by microflora (bacteria) in the colon. In such biodegradable systems, suitable polymers include, but are not limited to, azopolymers, linear segmented polyurethanes containing azo groups, polygalactomannans, pectin, glutaraldehyde-crosslinked dextran, polysaccharides, amylose, guar gum, pectin, chitosan, inulin, cyclodextrins, chondroitin sulfate, dextrans, locust bean gum, chondroitin sulfate, chitosan, poly(caprolactone), polylactic acid, and a copolymer of lactic and glycolic acids.

[00758] According to certain embodiments of such oral administration of compositions comprising one or more ASBTIs or other compounds described herein, the compositions are delivered to the colon without absorption in the upper intestine by coating the dosage forms with redox sensitive polymers that are degradable by the microflora (bacteria) of the colon. In such biodegradable systems, such polymers include, as a non-limiting example, redox sensitive polymers containing an azo and/or disulfide bond in the backbone.

[00759] In some embodiments, compositions formulated for delivery to the colon and/or rectum are formulated for sustained release. In some embodiments, sustained release formulations are resistant to the acidic environment of the stomach, thereby delaying the release of enteroendocrine peptide secretagogues until the dosage form reaches the colon and/or rectum.

[00760] According to certain embodiments, the slow-release formulations described herein comprise a capsule (containing an enteroendocrine peptide secretagogue and an optional absorption inhibitor) with a hydrogel plug. According to certain embodiments, the capsule and hydrogel plug are closed with a water-soluble cap and the entire unit is coated with an enteric polymer. When the capsule enters the small intestine, the enteric coating dissolves and the hydrogel plug swells and displaces from the capsule over a period of time and the composition is released from the capsule. The amount of hydrogel is used to control the period of time for the release of the contents.

[00761] According to some embodiments, provided herein is an oral dosage form comprising a multilayer coating, wherein the coating comprises different layers of polymers having different pH sensitivities. As the coated dosage form moves through the gastrointestinal tract, the different layers dissolve depending on the pH value encountered. Polymers used in such formulations include, by way of non-limiting example, polymethacrylates with suitable pH dissolution characteristics, Eudragit® RL and Eudragit® RS (inner layer) and Eudragit® FS (outer layer). According to other embodiments, the dosage form is an enteric-coated tablet having an outer shell of hydroxypropyl cellulose or hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[00762] According to some embodiments, provided herein is an oral dosage form that comprises a coating of cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, dihydroxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid, and combinations thereof.

Combination therapy

[00763] In some embodiments, the methods provided herein comprise administering a compound (e.g., an ASBTI) or composition described herein in combination with one or more additional agents. In some embodiments, the present invention also provides a composition comprising a compound (e.g., an ASBTI) with one or more additional agents. Fat-soluble vitamins

[00764] According to some embodiments, the methods provided herein further comprise administering one or more vitamins. According to some embodiments, the vitamin is vitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin, thiamine, retinol, beta-carotene, pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.

[00765] According to some embodiments, the vitamin is a fat-soluble vitamin, such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherols, phylloquinone. According to a preferred embodiment, the fat-soluble vitamin is tocopherol polyethyleneglycol succinate (TPGS).

Partial external biliary diversion (PEBD)

[00766] According to some embodiments, the methods provided herein further include the use of partial external biliary diversion as a treatment for patients who have not yet developed liver cirrhosis. This treatment helps reduce the circulation of bile acids/salts in the liver to reduce complications and prevent the need for early transplantation in many patients.

[00767] This surgical procedure involves isolating a 10 cm segment of intestine to act as a bile duct (a channel for bile to pass through) from the rest of the intestine. One end of the channel is attached to the gallbladder and the other end is brought out into the skin to form a stoma (a surgically created opening through which waste passes). Partial external biliary diversion may be used for patients who do not respond to all forms of drug therapy, especially older and larger patients. This procedure may not help smaller patients, such as infants. Partial external biliary diversion may reduce the severity of itching and abnormally low blood cholesterol levels.

ASBTI and PPAR agonists

[00768] In various embodiments, the present invention provides methods of using combinations of ASBTIs with PPAR (peroxisome proliferator-activated receptor) agonists. In various embodiments, the PPAR agonist is a fibrate drug. In some embodiments, the fibrate drug is clofibrate, gemfibrozil, ciprofibrate, benzafibrate, fenofibrate, or various combinations thereof. In various embodiments, the PPAR agonist is aleglitazar, muraglitazar, tesaglitaza, saroglitazar, GW501516, GW-9662, a thiazolidinedione (TZD), an NSAID (e.g., IBUPROFEN), an indole, or various combinations thereof.

ASBTI and FXR drugs

[00769] In various embodiments, the present invention provides methods of using combinations of ASBTIs with drugs targeting the farnesoid X receptor (FXR). In various embodiments, the drug targeting FXR is avermectin B 1a, bepridil, fluticasone propionate, GW4064, glycidone, nicardipine, triclosan, CDCA, ivermectin, chlorotrianisene, tribenoside, mometasone furoate, miconazole, amiodarone, butoconazole, bromocriptine mesylate, pizotifenmalate, or various combinations thereof. ASBTI and ursodiol

[00770] In some embodiments, the ASBTI is administered in combination with ursodiol or ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholic acid, glycouroxycholic acid. In some embodiments, increasing the concentration of bile acids/salts in the distal intestine causes intestinal regeneration, attenuation of intestinal damage, reduction of bacterial translocation, inhibition of free radical oxygen release, inhibition of proinflammatory cytokine production, or any combination or combination thereof.

[00771] According to certain embodiments, the patient is administered ursodiol at a daily dose of about or at least about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, 2250 mg, 2500 mg, 2750 mg or 3000 mg. According to certain embodiments, ursodiol is administered to a patient at a daily dose of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, 2250 mg, 2500 mg, 2750 mg, 3000 mg, or 3500 mg. According to various embodiments, ursodiol is administered to a patient in a daily dose of about or at least about 3 mg to about 300 mg, about 30 mg to about 250 mg, about 36 mg to about 200 mg, about 10 mg to about 3000 mg, about 1000 mg to about 2000 mg, or about 1500 to about 1900 mg.

[00772] In various embodiments, ursodiol is administered as a tablet. In various embodiments, ursodiol is administered as a suspension. In various embodiments, the concentration of ursodiol in the suspension is from about 10 mg/mL to about 200 mg/mL, from about 50 mg/mL to about 150 mg/mL, from about 10 mg/mL to about 500 mg/mL, or from about 40 mg/mL to about 60 mg/mL. According to various embodiments, the concentration of ursodiol in the suspension is about or at least about 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55 mg/mL, 60 mg/mL, 65 mg/mL, 70 mg/mL, 75 mg/mL, or 80 mg/mL. According to various embodiments, the concentration of ursodiol in the suspension is no more than about 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55 mg/mL, 60 mg/mL, 65 mg/mL, 70 mg/mL, 75 mg/mL, 80 mg/mL, or 85 mg/mL.

[00773] The ASBTI and the second active ingredient are administered such that the combination is present in a therapeutically effective amount. This therapeutically effective amount results from the administration of a combination of the ASBTI and another active ingredient (e.g., ursodiol), each administered in a therapeutically effective amount, or by virtue of additive or synergistic effects resulting from the combined administration, each may also be administered in a subclinical therapeutically effective amount, i.e., in an amount that, if administered alone, provides reduced effectiveness for the therapeutic purposes described herein, so long as the combined administration is therapeutically effective. In some embodiments, the administration of a combination of the ASBTI and any other active ingredient as described herein includes combinations in which the ASBTI or other active ingredient is present in a therapeutically effective amount and the other is present in a subclinical therapeutically effective amount, so long as the combined administration is therapeutically effective by virtue of their additive or synergistic effects. As used herein, the term "additive effect" describes a combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effects of each agent given alone. A synergistic effect is an effect in which the combined effect of two (or more) pharmaceutically active agents is greater than the sum of the effects of each agent given alone. Any suitable combination of ASBTI with one or more of the above-mentioned other active ingredients and optionally with one or more other pharmacologically active substances is considered to be within the scope of the methods described herein.

[00774] According to some embodiments, the specific choice of compounds depends on the diagnosis of the treating physicians and their assessment of the individual's condition and the appropriate treatment protocol. The compounds are optionally administered simultaneously (e.g., simultaneously, substantially simultaneously, or as part of the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or condition, the individual's condition, and the actual choice of compounds used. In some cases, determining the order of administration and the number of times each therapeutic agent is administered during the treatment protocol is based on an assessment of the disease being treated and the individual's condition.

[00775] In some embodiments, therapeutically effective dosages vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature.

[00776] In some embodiments of the combination therapies described herein, the dosages of the co-administered compounds vary depending on the type of co-administered drug, the particular drug administered, the disease or condition being treated, etc. Furthermore, when co-administered with one or more biologically active agents, a compound provided herein is optionally administered either simultaneously with the biologically active agent(s) or sequentially. In some cases, if administered sequentially, the treating physician will decide on the appropriate sequence of the therapeutic compound described herein in combination with the additional therapeutic agent.

[00777] The multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are optionally administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents are optionally provided in a single unit form or in multiple forms (by way of example only, either as a single pill or as two separate pills). In some cases, one of the therapeutic agents is optionally administered in multiple doses. In other cases, both are optionally administered in multiple doses. If not simultaneously, the time between multiple doses is any suitable time; for example, from greater than zero to less than four weeks. Furthermore, combination methods, compositions, and formulations are not to be limited to the use of only two agents; multiple therapeutic combinations (including two or more compounds described herein) are also contemplated.

[00778] According to certain embodiments, the dosage regimen for treating, preventing, or ameliorating the condition(s) from which relief is sought varies according to a variety of factors. These factors include the disorder from which the subject suffers, as well as the age, weight, gender, diet, and medical condition of the subject. Thus, according to various embodiments, the actual dosage regimen used varies and deviates from the dosage regimens set forth herein.

[00779] In some embodiments, the pharmaceutical agents comprising the combination therapy described herein are provided in a combination dosage form or in separate dosage forms intended to be administered substantially simultaneously. In certain embodiments, the pharmaceutical agents comprising the combination therapy are administered sequentially, with any therapeutic compound being administered in a regimen requiring two-step administration. In some embodiments, the two-step administration regimen requires sequential administration of the active agents or separate administration of the individual active agents. In certain embodiments, the time period between multiple administration steps varies, by way of non-limiting example, from several minutes to several hours, depending on the properties of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile of the pharmaceutical agent.

[00780] In certain embodiments, provided herein are combination therapies. In certain embodiments, the compositions described herein comprise an additional therapeutic agent. In certain embodiments, the methods described herein comprise administering a second dosage form comprising an additional therapeutic agent. In certain embodiments of combination therapies, the compositions described herein are administered as part of a regimen. Accordingly, the additional therapeutic agents and/or the additional pharmaceutical dosage form may be administered to a patient directly or indirectly, simultaneously or sequentially with the compositions and formulations described herein. Kits

[00781] According to another aspect, provided herein are kits comprising a rectal administration device prefilled with a pharmaceutical composition as described herein. In certain embodiments, the kits comprise an oral administration device and a pharmaceutical composition as described herein. In some embodiments, the kits comprise a prefilled bag or bottle for oral administration, while in other embodiments, the kits comprise prefilled bags for administering rectal gels. In certain embodiments, the kits comprise prefilled syringes for administering oral solutions, while in other embodiments, the kits comprise prefilled syringes for administering rectal gels. In some embodiments, the kits comprise prefilled pressurized cartridges for administering rectal foams.

Release in the distal ileum and/or colon

[00782] According to certain embodiments, the dosage form comprises a matrix (e.g., a matrix comprising hypermellose) that provides controlled release of the active agent in the distal jejunum, proximal ileum, distal ileum, and/or colon. According to some embodiments, the dosage form comprises a polymer that is pH sensitive (e.g., MMX™ matrix from Cosmo Pharmaceuticals) and provides controlled release of the active agent in the ileum and/or colon. Examples of such pH-sensitive polymers suitable for controlled release include, but are not limited to, polyacrylic polymers (e.g., anionic polymers of methacrylic acid and/or methacrylic acid esters, such as Carbopol® polymers) that contain acidic groups (e.g., -COOH, _-SO3H ) and swell to the alkaline pH of the intestine (e.g., pH from about 7 to about 8). In some embodiments, a dosage form suitable for controlled release in the distal ileum comprises an active agent in the form of microparticles (e.g., a micronized active agent). In some embodiments, a non-enzymatically degradable copolymer of lactic and glycolic acids (PLGA) core is suitable for delivering an ASBTI to the distal ileum. In some embodiments, the dosage form comprising the ASBTI is coated with an enteric polymer (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, anionic polymers of methacrylic acid, esters of methacrylic acid, etc.) for site-specific delivery to the ileum and/or colon. In some embodiments, bacterially activated systems are suitable for targeted delivery to the ileum. Examples of activated microflora systems include dosage forms comprising pectin, galactomannan, and/or azohydrogels and/or glycoside conjugates (e.g., conjugates of D-galactoside, β-D-xylopyranoside, or the like) of the active agent. Examples of gastrointestinal microflora enzymes include bacterial glycosidases such as, for example, D-galactosidase, β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase, etc.

[00783] The pharmaceutical solid dosage forms described herein optionally include an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoam, antioxidant, preservative, or one or more combinations thereof. In some aspects, a film coating is applied around the ASBTI formulation using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, a compound described herein is in the form of a particle and some or all of the particles of the compound are coated. In some embodiments, some or all of the particles of the compound described herein are microencapsulated. In some embodiments, the particles of the compound described herein are not microencapsulated and do not have a coating.

[00784] An ASBT inhibitor can be used in the preparation of medicaments for the prophylactic and/or therapeutic treatment of cholestasis or cholestatic liver disease. A method of treating any of the diseases or conditions described herein in an individual in need of such treatment can comprise administering pharmaceutical compositions comprising at least one ASBT inhibitor described herein or a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite thereof, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof in therapeutically effective amounts for said individual.

EXAMPLES

[00785] The following examples are presented to further describe some of the embodiments disclosed herein. The examples are intended to be illustrative and not limiting to the disclosed embodiments.

Example 1. Phase 2 open-label study of the efficacy and safety of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with progressive familial intrahepatic cholestasis (INDIGO clinical trial)

[00786] The dosing regimen used in the INDIGO clinical study is summarized in Figure 2. In addition to the doses shown in Figure 2, some patients were administered a dose of 280 mcg/kg twice daily (BID) after an initial dose of 280 mcg/kg daily (QD). The dose was escalated to 280 mcg/kg QD over 8 weeks.

[00787] The primary inclusion criteria for the INDIGO clinical trial were: 1) age 1 to 18 years; 2) clinical diagnosis of PFIC; 3) two mutant alleles of ABCB11 or ATB8B1. The primary exclusion criteria for the INDIGO clinical trial were: 1) surgical disruption of the enterohepatic circulation; 2) liver transplantation; 3) decompensated liver cirrhosis.

[00788] The following biomarkers of cholestasis were monitored in the INDIGO clinical study, among others: serum bile acid (sBA) concentration; serum alanine aminotransferase (ALT) concentration; serum aspartate aminotransferase (AST) concentration; serum bilirubin concentration; and serum 7αC4 concentration. Fecal bile acid (fBA) concentration was also measured. Pruritus severity was assessed throughout the INDIGO clinical study using observer-reported weekly mean scratch scores (ITCHRO(OBS)) (electronic diary completed by parents) and the Clinical Scratch Scale (CSS) (investigator-assessed). Patients were also assessed for health-related quality of life (HRQoL) throughout the INDIGO clinical study. The HRQoL used was the Pediatric Patient Quality of Life (PedsQL) survey. A multivariable response was defined as a decrease or normalization of sBA concentration by more than 70% and a decrease of more than 1.0 or less than 1.0 in the ITCHRO(OBS) score.

[00789] Table 1 provides a summary of demographic and baseline health-related parameters for participants in the INDIGO clinical trial. Of the 25 participants with PFIC 2, 19 participants had non-truncating ABCB11 mutations (classified as mild or moderate) and 6 participants had truncating ABCB11 mutations, see Tables 2–3 and 5. Twenty-nine participants reached week 48, see Table 4. Mild PFIC 2 was defined as PFIC 2 resulting from an E297G or D482G mutation in the ABCB11 gene, while moderate PFIC 2 was defined as PFIC 2 resulting from the ABCB11 gene containing missense mutations but not containing an E297G or D482G mutation, see Table 3. Nineteen participants had non-truncating ABCB11 mutations, 7 had mild PFIC 2, and 12 had moderate PFIC 2, see Table 3 and Table 5. One patient (1 of 7 patients with mild PFIC 2) with mild PFIC 2 was a multivariable responder in the INDIGO clinical trial at 280 mcg/kg QD, see Tables 3, 4 and 6. One patient (1 of 12 patients with moderate PFIC 2) with moderate PFIC 2 responded (high-dose responder) only to maralixibat 280 mcg/kg twice daily (discussed in more detail below), see Tables 3, 4 and 8. Five patients (5 of 12 patients with moderate PFIC 2) were responders in the INDIGO clinical trial at 280 mcg/kg/day at week 48 of the INDIGO clinical trial, see Tables 3-9. All patients with PFIC 1 and all patients with the ABCB11 truncating mutation did not represent multivariable responders in the INDIGO clinical trial, see Tables 3, 5 and Fig. 5.

[00790] Patients who did not respond in Table 3 did not respond at the time points and maximum doses listed in Table 6. Therefore, patients who did not respond may have responded if maralixibat was administered at a higher dose or for a longer period.

[00791] Therefore, given the above observations, patient response to maralixibat was correlated with patient genotype. In particular, the INDIGO clinical trial showed an unexpected result: only patients with PFIC 2 caused by a non-truncating mutation in the ABCB11 gene responded to maralixibat. Furthermore, it was unexpectedly found that patients with moderate PFIC 2 were more likely to respond to 280 mcg/kg/day maralixibat than patients with mild PFIC 2, see Tables 3 and 5-6.

[00792] Six patients responding to maralixibat 280 mcg/kg/day (low-dose responders) demonstrated reductions in sBA, serum ALT, serum bilirubin, ITCHRO(OBS) score, and PEDSQL score and increases in serum 7αC4 (C4) by week 48 of the INDIGO clinical trial, see Table 7. Two of the low-dose responders demonstrated reductions in sBA from baseline of greater than 70% or greater than 80%, see Table 9. Four of the low-dose responders demonstrated normalization of sBA, see Table 9. A detailed summary of each of the six low-dose maralixibat responders is presented in Fig. 3. All low-dose responders demonstrated at least a 2.5-fold increase in C4 from baseline within 13 weeks of the first maralixibat administration in the INDIGO clinical study. All low-dose responders demonstrated normalized or only slightly elevated serum ALT, AST, and bilirubin concentrations over time (e.g., 2-6 months after the first maralixibat administration) in the INDIGO clinical study.

[00793] Gastrointestinal infections have been found to interfere with

the therapeutic effect of maralixibat in PFIC 2, see Figs. 3D and 3E. Therefore, gastrointestinal infections may result in otherwise susceptible patients not responding to maralixibat administration.

[00794] Three patients with PFIC 2 truncation who did not respond to 280 mcg/kg/day maralixibat were given 560 mcg/kg/day maralixibat, and one (mentioned above) responded to the higher dose, see Tables 3 and 6.

[00795] Low-dose responders demonstrated 7αC4 concentrations at 48 weeks that were 14-fold greater than baseline (range 3-43). 7αC4 concentrations in non-responders were 1.8-fold greater than baseline (range 0.5-6) at 48 weeks. This demonstrates a correlation between response and increased BA synthesis. The mean change from baseline to week 48 in the ratio of 7αC4 to sBA concentration (7αC4:sBA) for low-dose responders was 1388-fold greater than baseline (range 5-3982), whereas the ratio was 1.9-fold greater than baseline (range 0.43-12) in non-responders. A high-dose responder demonstrated a 7αC4:sBA ratio 12-fold above baseline prior to administration of 560 mcg/kg/day maralixibat, which increased to 1770-fold above baseline upon administration of the higher dose.

[00796] Without being limited by any particular mechanism of action, patients with more preserved tubular transport (such as those with mild PFIC 2) may require higher doses of maralixibat to block LA absorption than patients with less preserved tubular transport. Additionally, patients with a biochemical response (increased 7αC4:sBA ratio) but not a clinical response may be rescued with higher doses of maralixibat.

[00797] Another unexpected result was observed in the INDIGO clinical trial. Low-dose responders demonstrated improved growth compared to baseline, while non-responders did not, see Figure 4. Growth improvement was measured using the height Z-score and was defined as a positive change in height Z-score compared to baseline height Z-score measured prior to maralixibat administration. In addition, the high-dose responder also demonstrated an increase in height Z-score after responding to sBA treatment.

[00798] Twelve patients participated in the long-term extension of the INDIGO clinical study. Figures 5-8 show cholestasis marker measurements taken for all participants in the INDIGO clinical study over time. The high-dose responder was initially administered a daily dose of 560 mcg/kg/day (2 equal doses of 280 mcg/kg daily, BID) between Days 547 and 638, see Figure 5A. The high-dose responder demonstrated an increase in the 7αC4:sBA ratio after administration of the higher dose, see Figure 8. A low-dose responder demonstrated an increase in sBA, a decrease in serum 7αC4, and a decrease in the 7αC4:sBA ratio during the long-term extension of the higher dose of maralixibat (280 mcg/kg BID) between days 640 and 730, see Figs. 5A and 6-8. Following the higher dose, sBA decreased, pruritus severity decreased, serum 7αC4 increased, and the 7αC4:sBA ratio increased, see Figs. 5A and 6-8. One low-dose responder demonstrated an increase in sBA during the long-term extension and was therefore started on the higher dose of maralixibat (280 mcg/kg twice daily) between days 820 and 910, see Fig. 6. Pruritus severity subsequently improved, see Fig. 6, and the 7αC4:sBA ratio increased, see Fig. 8.

[00799] In the long-term extension of the INDIGO clinical study, none of the patients with tenABCB11 truncating mutation responded, see Fig. 5B.

[00800] One non-responder demonstrated an initial increase in the 7αC4:sBA ratio up to day 90, which subsequently decreased, see Figure 8. This non-responder may have demonstrated a response if the non-responder had been administered a higher dose of maralixibat (e.g., 280 mcg/kg twice daily) prior to exclusion from the INDIGO clinical trial. The initial increase or spike in the 7αC4:sBA ratio indicates that this patient may have demonstrated a response (i.e., clinical response) to maralixibat administration.

[00801] Responder patients in the INDIGO study maintained response to maralixibat for more than a year and up to or greater than 5 years, see Figs. 5-8. Patients with persistent BSEP deficiency demonstrated durable control of pruritus and cholestasis with maralixibat, see Figs. 5-8. Figs. 5-8 show that the 7αC4:sBA ratio is a good predictor of response to ASBTI.

[00802] Responders had genotypes consistent with residual BSEP function, whereas some non-responders had genotypes consistent with complete absence of BSEP function.

Example 2: Dose-dependent excretion of faecal bile acids with the apical sodium-dependent bile acid transporter inhibitors maralixibat and volixibat in a phase 1 dose-finding clinical trial (NTC02475317) in overweight and obese adults.

[00803] Multiple oral doses of maralixibat, volixibat, or placebo were administered once (QD) or twice (BID) for 7 days to overweight and obese adults on a low-fiber diet. Participants had a body mass index of 25 kg/ ^m2 to 35 kg/ ^m2 . Participants consumed a low-fiber diet (<10 mg/day) for 2 days prior to randomization and during the 7-day treatment period. Measurements of fBA, sBA concentrations, and serum 7αC4 concentrations (a biomarker of bile acid synthesis) were obtained at pre-treatment and on day 7.

[00804] Summary demographic data and baseline fBA for participants administered each drug at each indicated dosage are presented in Table 10. Overall demographic data for all patients participating in the study are also presented in Table 10.

[00805] Of the 84 participants, 50 were randomized to maralixibat, 20 to volixibat, and 14 to placebo, see Table 10. All participants completed the study. Mean baseline fBA excretion ranged from 138 to 240 μM (SD, 92-231) across maralixibat doses and from 161 to 263 μM (SD, 130-288) across all volixibat doses, and was 246 μM (SD, 114) for placebo, see Table 10.

[00806] fBA excretion increased in a dose-dependent manner for maralixibat and volixibat, with no significant change for placebo, see Figure 9. The mean change from baseline was similar at the highest doses of maralixibat: 1251 μmol (95% CI, 539-1963) for 50 mg BID and 1144 μmol (95% CI, 823-1466) for 100 mg QD, see Figure 9. At the 10 mg dose, for maralixibat and volixibat, the mean changes from baseline were 515 μmol (95% CI, 196-835) and 744 μmol (95% CI, 230-1257), respectively, see Figure 9. 9. At the 20 mg dose, for maralixibat and volixibat, the mean change from baseline was 532 μmol (95% CI, 60–1005) and 874 μmol (95% CI, 457–1290), respectively, see Fig. 9.

[00807] Mean serum 7αC4 increased with maralixibat or volixibat, with the greatest change observed at the 50 mg BID dose of maralixibat, see Fig. 10.

[00808] There were no significant changes in sBA or 7αC4 compared with placebo, see Figures 9-10. Mean baseline sBA levels did not increase with maralixibat or volixibat, but increased by 2.6 ng/mL (95% CI 1.2-3.9) with placebo. All treatment-emergent adverse events were mild and none were serious. The proportion of participants with treatment-emergent adverse events did not differ between volixibat and maralixibat doses or between maralixibat and volixibat. The only treatment-emergent adverse events occurring in greater than 10% of participants were headache and diarrhea.

[00809] The increase in fBA excretion was dose dependent up to the highest doses tested of volixibat and maralixibat, see Fig. 9. Safety results were similar across all dose ranges tested and between compounds.

[00810] At the highest daily doses of maralixibat, the increase in fBA excretion was numerically greater at 50 mg BID than at 100 mg QD, see Fig. 9.

Example 3. Safety and efficacy of maralixibat in participants with primary sclerosing cholangitis (PSC): a 14-week, single-arm, open-label, phase 2a, proof-of-concept study of maralixibat (CAMEQ clinical trial; ClinicalTrials.gov: NTC02061540)

[00811] The CAMEO clinical trial included a 6-week dose escalation period (maralixibat 0.5 mg/day, 1 mg/day, 2.5 mg/day, 5 mg/day, and 7.5 mg/day) followed by an 8-week maintenance dose period (maralixibat 10 mg/day) and a 4-week observation period.

[00812] Participants were adults aged 18-80 years with a diagnosis of PSC. A diagnosis of PSC included a documented history of alkaline phosphatase (ALP) levels greater than 1.5 times the upper limit of normal, biliary obstruction, and histologic findings consistent with a diagnosis of PSC (if biopsy had been performed previously). A total of 27 adults participated in the study.

[00813] Efficacy was assessed by measuring sBA concentrations, serum 7αC4 concentrations (a marker of de novo bile acid synthesis), serum autotaxin concentrations, LDL-C concentrations, serum total cholesterol concentrations, serum liver enzyme concentrations, and pruritus severity at baseline and throughout the study. Pruritus severity was determined by calculating Adult Pruritus Ratings weekly sum scores and daily average scores (average over a 7-day period). Participants self-reported ITCHRO daily on a scale of 0 to 10 (0 = no pruritus; 10 = worst pruritus).

[00814] The mean baseline serum alkaline phosphatase concentration for participants in the CAMEO study was 471.6 U/L (SD, 316.9).

[00815] Outcomes were assessed in the overall study population and in subgroups of participants (A) with any pruritus at baseline or (B) with a mean daily ITCHRO score ≥4 out of 10 at baseline. Efficacy endpoints were based on change from baseline to week 14 or early discontinuation (ET) and were analyzed using paired t-tests or Wilcoxon signed-rank tests.

[00816] Of the 27 enrolled participants, 23 (85.2%) completed the study. Participants were predominantly male (66.7%) and white (85.2%) with a mean age of 43.7 years (standard deviation [SD], 11.35) at study entry. The mean time since PSC diagnosis was 94 months (SD, 75.4). PSC symptoms of inflammatory bowel disease and ulcerative colitis were reported by 44.4% and 55.6% of participants, respectively.

[00817] Total weekly ITCHRO scores decreased from baseline by 51% (p=0.0495) overall, by 53% (p=0.0275) in participants with any pruritus at baseline (n=18), and by 70% (p=0.0313) in participants with a daily ITCHRO score ≥4 out of 10 at baseline (n=6), see Figure 11. Average daily ITCHRO score improved by >3 points in 6 of 27 (22.2%) participants and by >1 point in 8 of 27 (29.6%) participants. No participant experienced a worsening of pruritus by more than 1 point from baseline to Week 14. Pruritus improved in all 6 participants with a baseline ITCHRO score ≥4, see Table 11 and Figure 11.

[00818] sBA decreased from baseline by 38% (mean -14.8 μmol/L [SD, 31.4]; p=0.0043) overall and by 45% in participants with a mean daily ITCHRO score ≥4 at baseline, see Fig. 12. Mean 7αC4 increased from baseline by 130% (mean 11.1 ng/mL [SD, 13.6]; p<0.0001) overall and by 107% in participants with a mean daily ITCHRO score ≥4 at baseline, see Fig. 12.

[00819] In the overall population of participants in the CAMEO clinical trial, significant reductions in serum autotaxin concentrations (-148 ng/mL [SD, 319]; P=0.0462) and serum LCL-C concentrations (-16.3 mg/dL [SD, 17.6]; P<0.0001) were observed, see Fig. 13. Participants with a mean daily ITCHRO score ≥4 at baseline had significant reductions in autotaxin levels, see Fig. 13. A reduction in total cholesterol was observed in the overall population (mean change, -21.2 mg/dL [SE, 4.90; SD, 25.5]; p=0.0002) and in participants with a mean daily ITCHRO ≥4 at baseline (mean change, -32.0 mg/dL [SE, 13.38]; p=0.06).

[00820] Mean conjugated bilirubin increased by 0.19 mg/dL (SE, 0.09, p<0.0462; SE, 0.450) in the overall population, with no significant change in participants with daily ITCHRO ≥0 at baseline. Changes in serum total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were not statistically significant in participants in the CAMEO clinical trial.

[00821] Statistically significant reductions in pruritus and sBA were observed after 14 weeks of treatment with maralixibat in the CAMEO clinical study, consistent with the proposed mechanism of action of maralixibate, see Figure 1. Serum autotaxin, a potential marker for cholestatic pruritus, was also statistically significantly improved, see Figure 13. The mean percentage reductions in pruritus and sBA and autotaxin were greater in participants with a mean daily ITCHRO score ≥4 at baseline than in the overall CAMEO study population, see Figure 14.

[00822] A statistically significant decrease in serum LDL-C and a statistically significant increase in serum 7αC4 indicate de novo synthesis of bile acids from cholesterol, consistent with inhibition of ASBT.

[00823] Maralixibat was well tolerated in the CAMEO study and was associated with reductions in serum BA levels in adults with PSC. In addition, autotaxin levels were reduced and pruritus was significantly improved compared with BL, with the greatest reductions in those with the worst pruritus at baseline.

Example 4. Durability of long-term treatment with maralixibat in children with Alagille syndrome: efficacy results from a phase 2b, 4-year, double-blind, randomized, placebo-controlled, drug withdrawal study with a long-term open-label pre-treatment period with maralixibat 400 mcg/kg/day twice daily (BID) (ICONIC clinical trial)

[00824] Children 1-18 years of age with a diagnosis of ALGS and evidence of cholestasis were eligible to participate in the ICONIC clinical trial, see Tables 12-14. During the long-term extension, participants with sBA above the upper limit of normal and/or ITCHRO(OBS) >1.5 were eligible for the 400 mcg/kg BID dose (all participants received the 400 mcg/kg BID dose). Inclusion criteria for the ICONIC study included the presence of cholestasis, which was defined as at least one of the following: 1) sBA (total sBA) >3 times the upper limit of normal, 2) serum conjugated bilirubin >1 mg/dL, 3) fat-soluble vitamin deficiency not otherwise explained, 4) serum gamma-glutamyl transferase >3 times the upper limit of normal, and 3) intractable pruritus that could only be explained by liver disease. Inclusion criteria also included the presence of significant pruritus, which was defined as a mean daily ITCHRO(OBS) score >2 for 2 consecutive weeks (0 = no pruritus; 4 = most severe pruritus). Exclusion criteria included surgical disruption of the enterohepatic circulation, liver transplantation, decompensated cirrhosis, or any liver disease other than ALGS.

[00825] sBA responders were defined as patients who achieved ≥50% reduction from baseline in sBA at Week 12 or Week 18. ITCHRO responders were defined as patients who achieved at least a 1-point reduction from baseline in the weekly average morning ITCHRO(OBS) scores at Week 12 or Week 18.

[00826] A summary of the experimental design of the ICONIC clinical study is presented in Fig. 15. Following completion of the 48-week pivotal study at 400 mcg/kg daily (QD), participants could continue long-term treatment with maralixibat at 400 mcg/kg QD (extension study). In the open-label extension study, the effect of higher doses was investigated by escalating the dose to a maximum of 400 mcg/kg BID in eligible participants.

[00827] Efficacy endpoints were based on changes from baseline in sBA concentrations, weekly mean ITCHRO(OBS) scores (0, none; 4, most severe), CSS scores (0, none; 4 most severe), and Clinical Xanthoma Rating Scale scores (0, none; 4, disabling). Differences in sBA concentrations and ITCHRO(OBS) scores between maralixibat and placebo were assessed during the randomized withdrawal period (weeks 18-22). Efficacy assessments were performed every 12 weeks during the long-term extension. Serum total cholesterol and serum 7αC4 concentrations, among others, were also monitored during the ICONIC clinical trial.

[00828] SBA was measured using a fully validated liquid chromatography-electrospray ionization-electrospray mass ionization (LC-ESI-MS) method using stable isotope dilution analysis to measure serum concentrations of the major bile acids (cholic, chenodeoxycholic, ursodeoxycholic, deoxycholic acid, lithocholic, and their corresponding glycine-taurine conjugates). Serum samples were analyzed in the Department of Pathology and Laboratory Medicine at Cincinnati Children's Hospital Medical Center in accordance with SOP #PATH.CMS.1033. Individual bile acid calibration standards ranged from 50-25,000 ng/mL, and quality control samples were prepared at concentrations of 100, 500, 1000, 2500, and 20,000 ng/mL. The intra- and interassay measurement imprecision of individual bile acids was within accepted GLP quality assurance guidelines and was <15% CV for these QC samples. The lower limit of quantification of the assay was set at 100 ng/mL and the imprecision at this concentration was <20%. The detection limit of the assay was 5 ng/mL. Total sBAs are the sum of the individual bile acid forms measured.

[00829] Of the 28 participants who completed the main study (through week 48), 23 consented to the long-term extension. After 2 years, 15 participants continued in the extension phase with a dose escalation to 400 mcg/kg BID, see Figs. 15-16. Table 14 presents the baseline characteristics and demographics of the long-term extension participants.

[00830] sBA concentrations decreased by 31% (p=0.0005) during the first 18 weeks of treatment with maralixibat 400 mcg/kg QD, see Figs. 17-18 and 32. During randomized withdrawal, sBA levels returned to baseline in the placebo group but remained stable in the maralixibat groups (least squares mean difference [LS], -114.0; SE, 48.0; p=0.03), see Figs. 17-18 and 32. The reduction in sBA levels was maintained and continued to improve over time, see Figs. 18 and 19. At 191 weeks, sBA levels had decreased by approximately 57% from baseline (p=0.0047), see Fig. 19.

[00831] Both serum total cholesterol and serum 7αC4 concentrations showed statistically significant reductions from baseline at weeks 48 and 191, see Table 15. The statistically significant reductions in serum total cholesterol and serum 7αC4 concentrations observed at week 49 were maintained through week 191 of the ICONIC clinical study, see Table 15.

[00832] ITCHRO(OBS) scores decreased from baseline (mean change -1.7; SE, 0.2; p<0.0001) during the first 18 weeks of treatment with maralixibat 400 mcg/kg QD, see Figs. 20, 23, and 32. During randomized withdrawal, pruritus increased in the placebo group but not the maralixibat group (LS mean difference, -1.5; SE, 0.3, p=0.0001), see Figs. 20, 21, 23, 25, and 32 and Table 16. At week 191, ITCHRO(OBS) score decreased from baseline (mean change -2.5; SE, 0.2; p<0.0001), see Figs. 22-23. Reduction in pruritus was also demonstrated by a mean reduction in CSS score at week 191 of 2.4 points (SE, 0.4; p<0.0001), Figure 22, and a mean reduction in ITCHRO(OBS) score at week 193 of more than 2 points to a final score of approximately 0.33 (SE, 0.2; p<0.0001), see Figures 23 and 24. In addition, CSS scores decreased by more than 1.5 points (final mean score of approximately 1.5) on average by week 48 across all participants, Figure 22, and ITCHRO(OBS) scores decreased by more than 1.5 points on average (final mean score of approximately 0.33) from baseline by week 193, see Figure 23 and 24. Pruritus control improved over time: more than 89% of study days in all participants had observers reporting minimal or no pruritus (ITCHRO(OBS) ≤1) at 98 weeks, see Figs. 21–25.

[00833] The reduction in sBA concentrations and pruritus severity continued and further improved during the extension, see Figs. 18-19 and 22-24, and xanthomas continued to be reabsorbed (p<0.05), see Fig. 29. CSS scores continued to improve during the extension (p<0.0001). Improvements were seen in PedsQL multidimensional fatigue scale scores (p<0.01) during the main study and the ICONIC extension, see Figs. 26-27. Thus, maralixibat improved quality of life.

[00834] Clinical Xanthoma Score was reduced by 0.7 points (SE, 0.3; p=0.0285) from baseline in ICONIC clinical trial participants at week 19. Clinical Xanthoma Score was significantly improved (p<0.01) in all participants at week 48, see Figure 28. Xanthomas continued to be reabsorbed over an extended period of time, see Figure 29. Thus, maralixibat improved xanthomas.

[00835] Maralixibat was well tolerated during the pivotal study and the ICONIC clinical study extension over three years. Treatment effects were maintained over 48 weeks. Serum GGT, ALT, AST, and bilirubin concentrations were monitored throughout the ICONIC clinical study, see Figure 30.

[00836] The therapeutic benefits of maralixibat in children with ALGS were clinically meaningful and statistically significant. Continuation of maralixibat treatment after the washout period maintained significantly lower sBA levels and less pruritus than placebo during the randomized, placebo-controlled washout period. Maralixibat significantly reduced pruritus and sBA levels over time compared with placebo in children with ALGS. Long-term treatment with maralixibat was associated with sustained control of sBA levels, pruritus, and xanthomas, as well as improved growth (discussed in more detail below). Maralixibat was generally well tolerated at doses up to 800 mcg/kg/day and with treatment durations up to 4 years.

[00837] A positive correlation was observed between the decrease in sBA concentration and the reduction in pruritus severity as measured by the ITCHRO(OBS) scale, see Figs. 31-32 and Tables 17-19.

[00838] Height Z-score increased by 0.5 (SE, 0.1; p=0.0027) compared to baseline in participants in the ICONIC clinical trial, see Figs. 33-34. This corresponds to a statistically significant acceleration of growth in height. Therefore, maralixibat improved height compared to baseline in patients with ALGS. Moreover, further increases in height compared to baseline were observed when patients (N=15) were administered maralixibat 400 mcg/kg twice daily following administration of maralixibat 400 mcg/kg once daily for a period exceeding approximately 40 weeks. Additionally, further improvements in sBA, pruritus, and height were observed following administration of the higher daily dose compared to the improvements observed with maralixibat 400 mcg/kg once daily, see Fig. 18 and 23. The increase in height was also observed as an increase in weight Z-scores, see Figs. 35-36. Similar to height Z-scores, maralixibat administration produced a dose-dependent increase in weight Z-scores, see Figs. 35-36. Subjects administered maralixibat 400 mcg/kg twice daily following administration of 400 mcg/kg maralixibat once daily for over 40 weeks demonstrated greater increases in weight Z-scores at 400 mcg/kg twice daily than at 400 mcg/kg QD.

[00839] All references cited anywhere in this specification are herein incorporated by reference in their entirety for all purposes.

[00840] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are presented by way of example only.

[00841] The recitation of ranges of values herein is merely intended to serve as a shorthand way of referring to each individual value falling within the range and each endpoint unless otherwise stated herein, and each individual value and endpoint is included in the description as if it were individually read herein.

[00842] Numerous variations, changes and substitutions will now be apparent to those skilled in the art without departing from the present invention. It will be appreciated that various alternatives to the embodiments of the present invention described herein may be used in practicing the present invention. It is intended that the following claims define the scope of the present invention and that the methods and structures within the scope of these claims and their equivalents are covered by them.

Claims (18)

1. Use of maralixibat chloride for the treatment of Alagille syndrome (ALGS) in a pediatric subject in need of such treatment, at a dose of 400 to 800 mcg/kg/day, in which the subject experiences pruritus prior to administration of maralixibat chloride. 2. Use of maralixibat chloride for the treatment of Alagille syndrome (ALGS) in a pediatric subject requiring such treatment, at 800 mcg/kg/day, in which the subject experiences pruritus prior to administration of maralixibat chloride. 3. Use according to claim 1, wherein maralixibat chloride is administered once daily (QD). 4. Use according to item 1, wherein maralixibat chloride is administered twice daily (BID). 5. Use according to claim 1, wherein maralixibat chloride is administered for at least 18 weeks. 6. Use according to claim 1, wherein maralixibat chloride is prescribed for at least 2 years. 7. Use according to claim 1, wherein maralixibat chloride is prescribed for at least 3 years. 8. The use according to claim 1, wherein the subject exhibits below-normal height or weight prior to administration of maralixibat chloride. 9. Use according to paragraph 1, where the subject is at least 1 year old. 10. Use according to item 1, wherein maralixibat chloride is administered before meals. 11. Use according to claim 1, wherein maralixibat chloride is administered orally. 12. Use of maralixibat chloride for the treatment of Alagille syndrome (ALGS) in a pediatric subject requiring such treatment, at 400 mcg/kg/day, in which the subject experiences pruritus prior to administration of maralixibat chloride.