RU2822484C2 - Methods for increasing height of pediatric patients with cholestatic liver disease - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to a method for increasing growth. Method of increasing height in a subject of child age suffering from cholestatic liver disease, comprising administering to the subject an effective amount of ASBTI, where ASBTI is

(maralixibate)

or a pharmaceutically acceptable alternative salt thereof, wherein ASBTI is administered in amount of 140 mcg/kg/day to 2000 mcg/kg/day.

EFFECT: use of the invention provides an increase in height in a child suffering from cholestatic liver disease.

35 cl, 36 dwg, 19 tbl, 4 ex

Description

Link to related applications

[0001] This application claims priority under 35 U.S.C. §119(e) Provisional U.S. Patent Application No. 62/804523, filed February 12, 2019, 62/863904, filed June 20, 2019, 62/ 908431, filed September 30, 2019, and 62/932015, filed November 7, 2019, which are incorporated herein by reference in their entirety for all purposes.

Field of technology to which the present invention relates

[0002] The present invention generally relates to methods of treating or alleviating cholestatic liver disease. In particular, the present invention relates to methods of increasing the height of pediatric patients suffering from cholestatic liver disease by administering an apical sodium-dependent bile acid transporter inhibitor (ASBTI).

BACKGROUND OF THE INVENTION

[0003] Hyperchoemia and cholestatic liver diseases are liver diseases associated with impaired bile secretion (ie, cholestasis), associated with, and often secondary to, intracellular accumulation of bile acids/salts in hepatocytes. Hypercholemia is characterized by an increased content of bile acids or bile salts in the blood serum. 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 is the result of constitutively impaired bile secretion, and secondary intrahepatic cholestasis, which results from hepatocellular damage. Primary intrahepatic cholestasis includes diseases such as benign recurrent intrahepatic cholestasis, which is a predominantly adult form with similar clinical symptoms, and progressive familial intrahepatic cholestasis (PFIC) types 1, 2, and 3, which affect children.

[0004] Pediatric cholestatic liver diseases affect a small percentage of children, but treatment results in significant health care costs each year. Currently, many cholestatic liver diseases in children require invasive and expensive treatments such as liver transplantation and surgery. There is no effective and less invasive treatment suitable for the pediatric population.

Brief Disclosure of the Present Invention

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

[0006] In one aspect, the present invention provides a method of increasing the height of a pediatric subject suffering from cholestatic liver disease, the method comprising administering to the subject an effective amount of ASBTI.

[0007] In some embodiments, ASBTI is

(GSK2330672) or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is maralixibat or a pharmaceutically acceptable alternative salt thereof. In various embodiments, ASBTI is volixibate or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is odevixibate or a pharmaceutically acceptable salt thereof. In some embodiments, ASBTI is elobixibate or a pharmaceutically acceptable salt thereof. In various embodiments, ASBTI is GSK2330672 or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), biliary atresia, Alagille syndrome (ALGS), intrahepatic cholestasis of pregnancy (ICP), or any cholestatic condition in children resulting in below-normal height or weight . In some embodiments, the cholestatic liver disease is biliary atresia. In various embodiments, the cholestatic liver disease is PFIC. In various embodiments, the PFIC is selected from PFIC type 1, PFIC type 2, and PFIC type 3. In some embodiments, the PFIC is PFIC type 2. In some embodiments, the subject has the ABCB11 gene with a missense mutation and a nontruncating mutation. In some embodiments, the cholestatic liver disease is ALGS. In various embodiments, the cholestatic liver disease is an ICP.

[0009] In various embodiments, ASBTI is administered once daily (QD). In some embodiments, ASBTI is administered in an amount of from about 140 μg/kg/day to about 1400 μg/kg/day. In various embodiments, ASBTI is administered twice daily (BID). In some embodiments, ASBTI is administered in an amount of from about 70 μg/kg to about 700 μg/kg per dose. In various embodiments, the increase in height is measured as an increase in Z-score of height or weight. In some embodiments, administration results in an increase in height or weight Z-score of at least 0.1 over baseline. In some embodiments, administration results in an increase in height or weight Z-score of at least 0.25 over baseline. In some embodiments, administration results in increased height within 1 year of the first ASBTI administration. In various embodiments, the increase in height or weight Z-score is maintained for a period of up to 20 weeks. In some embodiments, the increase in height or weight Z-score is maintained for a period of up to 2 years. In various embodiments, administration of ASBTI results in an increase in height or weight Z-score in a dose-dependent manner.

[0010] In some embodiments, administration of ASBTI results in a reduction in symptom or change in disease-related laboratory values of cholestatic liver disease that persists for at least 10 weeks. In various embodiments, the reduction of a symptom or change in disease-related laboratory parameters includes a decrease in sBA concentration, an increase in serum 7αC4 concentration, an increase in the ratio of serum 7αC4 concentration to sBA concentration (7aC4:sBA), a decrease in pruritus, an increase in a quality of life score, an increase fatigue-related quality of life indicator, height gain, or a combination of both. In various embodiments, a reduction in a symptom or a change in disease-related laboratory parameters is determined relative to a baseline.

[0011] In some embodiments, administration of ASBTI results in increased excretion of fBA. In various embodiments, administration of ASBTI results in a dose-dependent increase in fBA excretion. In some embodiments, ASBTI is administered at a dose sufficient to result in at least a 1.5-fold increase in fBA excretion over baseline.

[0012] 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

[0013] In FIG. Figure 1 is a schematic diagram summarizing the physiological effects of maralixibate administration in a patient. CYP7A1, cholesterol 7α-hydroxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor.

[0014] In FIG. Figure 2 is a flow chart providing an overview of the dosing schedule used in the phase 2 open-label clinical trial of the safety and efficacy of INDIGO (INDIGO Clinical Study) of maralixibate in children with PFIC. A clinical study examined long-term exposure to maralixibat.

[0015] In FIG. 3A-3F present quantitative summary results of response rates measured for six responding patients who participated in the INDIGO clinical trial. The six responders were: a girl aged 3 years (Figure 3A), a boy aged 10 years (Figure 3B), a girl aged 6 years and the boy's sister aged 10 years (Figure 3C), a girl aged 4 years (Fig. 3D), a boy aged 3 years (Fig. 3E) and a girl aged 1 year (Fig. 3F). In each of FIG. 3A-3F are three scatter plots depicting sBA content (concentrations), Pruritus Severity Score, and Pediatric Evaluating Quality of Life Questionnaire (PEDSQL) scores by study week, respectively. Itch severity score was measured according to the Clinical Scratch Score (CSS) and Itch Rating Outcome (ITCHRO) score. In each of FIG. 3A-3F also provide summary results of the changes observed in ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels, bilirubin levels and C4 levels for each responding patient.

[0016] In FIG. 4 is a correlation chart 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 60 weeks was due to one patient having missing measurements at that time point.

[0017] In FIG. 5A and 5B are correlation plots depicting serum bile acid (sBA) concentrations over time for patients who participated in the INDIGO clinical trial. In fig. Figure 5A plots sBA concentrations over time for patients with non-truncating mutations in the bile salt excretion pump (BSEP, which is encoded by the ABCB11 gene). In fig. Figure 5B plots sBA concentrations over time for patients with BSEP truncating mutations. In fig. 5A-5B show that sBA responses differed by BSEP mutation status. Black filled circles indicate termination. White filled circles indicate the start of BID dosing (280 μg/kg BID). In fig. 5A and 5B, lines corresponding to non-responding patients are marked with an asterisk.

[0018] In FIG. Figure 6 is a correlation graph depicting observer-reported weekly average itching outcome scores (ITCHRO(OBS)) for patients enrolled in the INDIGO clinical trial who had non-truncating BSEP mutations. In fig. Figure 6 shows that the ITCHRO(OBS) response was maintained over many years and that >50% (10/19) of patients demonstrated a ≥1.0 point reduction in the ITCHRO(OBS) score. Black filled circles indicate termination. White filled circles indicate the start of BID dosing (280 μg/kg BID). The ITCHRO(OBS) scale ranges from 0 to 4. In FIG. 6 lines corresponding to non-responding patients are marked with an asterisk.

[0019] In FIG. Figure 7 shows a correlation plot of mean serum concentrations of 7a-hydroxy-4-choesten-3-one (7αC4 or C4) over time for patients enrolled in the INDIGO clinical trial who had nontruncating BSEP mutations. In fig. 7 shows that responding patients with non-truncating BSEP mutations had a significant increase in 7αC4 concentrations. Black filled circles indicate termination. White filled circles indicate the start of BID dosing (280 μg/kg BID). The ITCHRO(OBS) scale ranges from 0 to 4. In FIG. 7 lines corresponding to non-responding patients are marked with an asterisk.

[0020] In FIG. 8 is a correlation chart showing the ratio of 7αC4 concentration to sBA concentration (7αC4:sBA) over time for patients participating in the INDIGO clinical trial who had non-truncating BSEP mutations. In fig. Figure 8 shows that responders with non-truncating BSEP mutations had significantly different 7αC4:sBA ratios than nonresponders. Two responders with non-truncating BSEP mutations showed an increase in 7αC4:sBA ratio after dose escalation. Black filled circles indicate termination. White filled circles indicate the start of BID dosing (280 μg/kg BID). The ITCHRO(OBS) scale ranges from 0 to 4. In FIG. 8 lines corresponding to non-responding patients are marked with an asterisk.

[0021] In FIG. Figure 9 is a bar graph showing the mean change from baseline in fecal bile acid (fBA) excretion on days 6 and 7 at the indicated doses of maralixibate, volixibate, and placebo for a phase 1, blinded, placebo-controlled, dose-finding clinical trial. (NCT02475317). BID, twice daily; QD, once daily; SE, standard error.

[0022] In FIG. 10 is a histogram showing the mean change in serum 7αC4 concentration from baseline to day 7 at the indicated doses of maralixibate, volixibate, and placebo. BID, twice daily; fBA, fecal bile acids; QD, once daily; SE, standard error.

[0023] In FIG. 11 is a bar graph showing weekly average 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 trial) with any pruritus at baseline and participants with daily ITCHRO scores ≥4 at baseline.

[0024] In FIG. Figure 12 shows histograms of sBA concentration (left panel) and 7αC4 concentration (right panel) in the general population participating in the CAMEO clinical trial and in participants with daily ITCHRO scores ≥4 at baseline.

[0025] In FIG. 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 daily ITCHRO scores ≥4 at baseline. level.

[0026] In FIG. Figure 14 shows a histogram of the percentage change from baseline to week 14 or early discontinuation for efficacy measures including ITCHRO (day 1–10 score), sBA concentration, and serum autotaxin concentration in six participants in the CAMEO clinical trial with measures per day ITCHRO ≥4 at baseline.

[0027] In FIG. 15 is a diagram summarizing the clinical study design for a double-blind, randomized, placebo-controlled drug withdrawal study with long-term open-label treatment with maralixibat 400 μg/kg QD (ICONIC clinical trial).

[0028] In FIG. Figure 16 is a chart summarizing the distribution of participants in the ICONIC clinical trial.

[0029] In FIG. 17A and 17B show significant improvements in sBA compared to baseline and placebo in participants in the ICONIC clinical trial. In fig. 17A shows a graph of the average change in sBA concentration from baseline for all participants through week 48. In fig. 17B is a histogram showing the mean change in sBA from weeks 8 to 22 in sBA responders during randomized withdrawal.

[0030] In FIG. 18 shows a graph of mean sBA concentrations for participants in the ICONIC clinical trial during the main study (first 48 weeks) and during the extension (period after 48 weeks). MRX = maralixibat; PLA = placebo.

[0031] In FIG. 19 is a histogram showing the mean change from baseline (BL) in sBA observed in the ICONIC clinical trial.

[0032] In FIG. 20A and 20B show improvements in ITCHRO(OBS) scores maintained during randomized withdrawal of maralixibate in participants in the ICONIC clinical trial. In fig. Figure 20A shows the average change in ITCHRO(OBS) from baseline for participants over time. In fig. 20B shows a plot of the ITCHRO(OBS) score for participants during the placebo-controlled treatment withdrawal period.

[0033] In FIG. 21A and 21B show improvements from baseline in Clinical Scratch Scale (CSS) scores throughout the ICONIC clinical trial. In fig. 21A shows the proportions of total patients who had CSS scores reported at baseline, week 18, and week 48. In fig. Figure 21B shows the proportions of total patients treated with maralixibat or placebo with CSS scores during the placebo-controlled treatment withdrawal period at week 22.

[0034] In FIG. Figure 22 shows the change from baseline (BL) in CSS for participants in the ICONIC clinical trial at week 48 and week 191.

[0035] In FIG. 23A-23D are graphs of weekly average ITCHRO(OBS) over time for participants in the ICONIC clinical trial during the main study and during the extension study. Fig. 23A is a correlation chart showing the average ITCHRO(OBS) over time. In fig. 23B showed that the reduction in itching was maintained over a long period of time. Each line represents ITCHRO(OBS) scores for an individual patient. In fig. 23C and 23D show that the reduction in pruritus was maintained by maralixibat, but not by the placebo withdrawal period (indicated by the rectangular area in the graph). Each line represents ITCHRO(OBS) scores for an individual patient. MRX = maralixibat; PLA = placebo. N = number of participants measured at the specified time point.

[0036] In FIG. Figure 24 shows the change from baseline (BL) in ITCHRO(OBS) at 48 weeks and 193 weeks for participants in the ICONIC clinical trial.

[0037] In FIG. 25 is a histogram showing the proportion of study days with ITCHRO(OBS) ≤1 among all participants (%) in the ICONIC clinical trial during placebo administration and during maralixibate administration.

[0038] In FIG. Figure 26 shows a histogram of HRQoL scores over time for patients participating in the ICONIC clinical trial. HRQoL scores were measured as PEDSQL scores.

[0039] In FIG. 27 is a bar graph showing the change from baseline (BL) in the PEDSQL Fatigue Scale score (0 to 100 scale) at week 48 and week 191 for participants in the ICONIC clinical trial, n = number of participants present at the indicated time point.

[0040] In FIG. Figure 28 shows a graph of Clinical Xanthoma Score scores over time for patients participating in the ICONIC clinical trial.

[0041] In FIG. 29 is a bar graph showing the change from baseline (BL) in Clinical Xanthoma Scale scores for participants in the ICONIC clinical trial at week 48 and week 191.

[0042] In FIG. 30 is a correlation chart showing serum concentrations of liver function indicators over time for participants in the ICONIC clinical trial. GGT, gamma-glutamyl transpeptidase.

[0043] In FIG. Figure 31 shows a graph of the percentage change in sBA from baseline as a function of the change in weekly average morning ITCHRO(OBS) from baseline for participants in the ICONIC clinical trial at week 48.

[0044] In FIG. 32A-32H show grid plots for each participant (identified by the subject number above each plot) in the ICONIC clinical trial through week 48. In fig. 32A-32H show grid plots of sBA concentration (blue; left axis; μmol/L) and weekly average ITCHRO(OBS) (red; right axis) over time (lower axis) for each participant in the ICONIC clinical trial. In fig. 32A and 32D show grid 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 drug withdrawal period in the ICONIC clinical trial. In fig. 32E and 32H show hash marks for patients in the MRX-Placebo-MRX study arm, which includes only those patients administered maralixib before, placebo during, and maralixib again after a placebo-controlled drug withdrawal period. Patient 090004 did not have any post-baseline assessments, so the baseline data point is not shown on the graph.

[0045] In FIG. 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 x-axis. BL = baseline.

[0046] In FIG. 34 shows a correlation chart of the mean change from baseline in height Z-score over time for participants in the ICONIC clinical trial who agreed to the long-term extension of the ICONIC clinical trial and remained in the study for approximately four years (n=15). The number of patients (N) measured at each data point is indicated below the x-axis. BL = baseline.

[0047] In FIG. Figure 35 shows a correlation plot of the mean change from baseline in weight 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.

[0048] In FIG. 36 shows a correlation chart 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 remained in the study for 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

[0049] 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. Moreover, each of the examples given in connection with various embodiments of the present invention are 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 the various ways to use the present invention.

[0050] Bile acids/salts play a critical role in the activation of digestive enzymes and the dissolution of fats and fat-soluble vitamins and are involved in diseases of the liver, biliary tract and intestines. Bile acids are synthesized in the liver through a multi-stage, multi-organellar 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, resulting in a carboxyl group at the end of the chain. The most common bile acids are cholic acid and chenodeoxycholic acid ("primary bile acids"). Before leaving the hepatocytes and producing 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.

[0051] Bile salts are excreted by hepatocytes into the tubules to form bile. The tubules 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 promotes metabolism and the breakdown of fats. Bile salts are reabsorbed in the terminal ileum and transported back to the liver through the portal vein. Bile salts often undergo multiple enterohepatic circulation before being excreted in the feces. A small percentage of bile salts can be reabsorbed in the proximal intestine by either passive or carrier-mediated transport processes. Most 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 ASBT is involved in the vectorial transport of bile acids/salts into the portal circulation. Completion of the enterohepatic circulation occurs at the basolateral surface of the hepatocyte through a transport process that is primarily mediated by the sodium-dependent bile acid transporter. Intestinal transport of bile acids 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 bile acid transport in the intestine.

[0052] Bile acid concentrations vary within the intestinal lumen, 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 damage caused by the accumulation of bile acids in the liver.

Classes of cholestatic liver disease in children

[0053] As used herein, the term “cholestasis” means a disease or symptoms involving impaired formation of bile and/or flow of bile. As used herein, the term “cholestatic liver disease” means liver disease associated with cholestasis. Cholestatic liver disease is often accompanied by jaundice, fatigue and itching. 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.

[0054] Cholestatic liver disease can be divided clinicopathologically into two main categories: obstructive, often extrahepatic, cholestasis and non-obstructive, or intrahepatic, cholestasis. In the first case, cholestasis occurs when the flow of bile is mechanically blocked, for example by gallstones or a tumor, or as in extrahepatic biliary atresia.

[0055] The latter group with non-obstructive intrahepatic cholestasis, in turn, is divided into two main subgroups. In the first subgroup, cholestasis occurs when the processes of secretion and modification of bile or the synthesis of bile components are involved in hepatocellular damage so severely that nonspecific impairment of many functions, including those that contribute to the formation of bile, can be expected. In the second subgroup, it is impossible to determine the presumed cause of hepatocellular damage. Cholestasis in such patients appears to occur when one of the steps in the secretion or modification of bile or the synthesis of bile components is constitutive damage. This cholestasis is considered primary.

[0056] Accordingly, methods and compositions are provided herein for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa, and/or enhancing adaptive processes in the intestine in individuals with cholestasis and/or cholestatic liver disease. In some such embodiments, the methods include increasing the concentration of bile acid and/or the concentration of GLP-2 in the intestinal lumen.

[0057] Hyperchoemia and elevated levels of AR (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma-GT (gamma-glutamyl transpeptidase) and 5'-nucleotidase are biochemical signs of cholestasis and cholestatic liver disease. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa, and/or enhancing adaptive processes in the intestine in individuals with hypercholeemia and elevated levels of AR (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma -GT (gamma-glutamyl transpeptidase or GGT) and/or 5'-nucleotidases. In some such embodiments, the methods involve increasing the concentration of bile acid in the intestinal lumen. In addition, provided herein are methods and compositions for reducing hyperchoemia and elevated AP (alkaline phosphatase), LAP (leukocyte alkaline phosphatase), gamma-GT (gamma-glutamyl transpeptidase) and 5'-nucleotidases by reducing the overall bile acid load in serum by excreting bile acid in feces.

[0058] Pruritus is often associated with cholestasis in pediatric patients and cholestatic liver disease in pediatric patients. It has been suggested that itching results from the action of bile salts on peripheral pain afferent nerves. The degree of itching depends on the individual (ie, some individuals are more sensitive to increased bile acids/salts). Administration of agents that reduce serum bile acid concentrations has been shown to reduce pruritus in some individuals. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa and/or enhancing adaptive processes in the intestine in individuals with pruritus. In some such embodiments, the methods involve increasing the concentration of bile acids in the intestinal lumen. In addition, provided herein are methods and compositions for the treatment of itching that reduce the total bile acid load in the serum by excreting bile acids in feces.

[0059] Another symptom of cholestasis in pediatric patients and cholestatic liver disease in pediatric patients is an increase in the concentration of conjugated bilirubin in the blood serum. Elevated serum concentrations of conjugated bilirubin cause jaundice and dark urine. The magnitude of the increase is not of diagnostic importance, since no relationship has been established between serum conjugated bilirubin levels and the severity of cholestasis and cholestatic liver disease. Conjugated bilirubin concentrations rarely exceed 30 mg/dL. Accordingly, methods and compositions are provided herein for stimulating epithelial proliferation and/or intestinal mucosal regeneration and/or enhancing intestinal adaptive processes in individuals with elevated serum conjugated bilirubin concentrations. In some such embodiments, the methods involve increasing the concentration of bile acid in the intestinal lumen. Also provided herein are methods and compositions for treating elevated serum conjugated bilirubin concentrations by reducing the total serum bile acid load by excreting bile acids in feces.

[0060] Elevated serum concentrations of unconjugated bilirubin are also considered diagnostic of cholestasis and cholestatic liver disease. Portions of serum bilirubin are covalently bound to albumin (delta-bilirubin or biliprotein). This fraction may constitute a large proportion of total bilirubin in patients with cholestatic jaundice. The presence of a large amount of delta-bilirubin indicates long-term cholestasis. Delta bilirubin in umbilical cord or newborn blood indicates childhood cholestasis/cholestatic liver disease that precedes birth. Accordingly, methods and compositions are provided herein for stimulating epithelial proliferation and/or intestinal mucosal regeneration and/or enhancing intestinal adaptive processes in individuals with elevated serum concentrations of unconjugated bilirubin or delta-bilirubin. In some such embodiments, the methods involve increasing the concentration of bile acids in the intestinal lumen. Also provided herein are methods and compositions for treating elevated serum concentrations of unconjugated bilirubin and delta-bilirubin by reducing the total serum bile acid load by excreting bile acids in feces.

[0061] Cholestasis and cholestatic liver disease in pediatric patients lead to hyperchoemia. 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, absorption of bile salts entering the liver into the portal vein blood is ineffective, resulting in leakage of bile salts into the peripheral circulation. Accordingly, provided herein are methods and compositions for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa, and/or enhancing adaptive processes in the intestine in individuals with hyperchoemia. In some such embodiments, the methods involve increasing the concentration of bile acids in the intestinal lumen. In addition, provided herein are methods and compositions for the treatment of hypercholemia that reduce the total bile acid load in the serum by excreting bile acids in feces.

[0062] 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 cholesterol metabolism and degradation. Cholesterol retention is associated with an increase in membrane cholesterol content and a decrease in 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 regeneration of the intestinal mucosa and/or enhancing intestinal adaptive processes in individuals with hyperlipidemia. In some such embodiments, the methods involve increasing the concentration of bile acids in the intestinal lumen. In addition, provided herein are methods and compositions for the treatment of hyperlipidemia that reduce the total bile acid load in the serum by excreting bile acids in feces.

[0063] In individuals with childhood cholestasis and childhood cholestatic liver disease, xanthomas develop as a result of the deposition of excess circulating cholesterol in the dermis. The development of xanthoma is more typical for obstructive cholestasis than for hepatocellular cholestasis. Flat xanthomas first appear around the eyes, then in the folds 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 adaptive processes in the intestine in individuals with xanthomas. In some such embodiments, the methods involve increasing the concentration of bile acids in the intestinal lumen. Also provided herein are methods and compositions for the treatment of xanthomas that reduce the total bile acid load in the serum by excreting bile acids in the feces.

[0064] In children with chronic cholestasis, one of the main consequences of childhood cholestasis and childhood cholestatic liver disease is developmental delay. Failure to grow is a consequence of decreased delivery of bile salts to the intestines, which contributes to ineffective digestion and absorption of fats, as well as decreased absorption of vitamins (vitamins E, D, K and A are not absorbed in cholestasis). Additionally, delivering fat to the colon can lead to colonic secretions and diarrhea. Treatment for developmental delay involves dietary replacement and supplementation of long-chain triglycerides, medium-chain triglycerides, and vitamins. Accordingly, methods and compositions are provided herein for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa and/or enhancing adaptive processes in the intestine in individuals (eg, children) with developmental disorders. In some such embodiments, the methods involve increasing the concentration of bile acids in the intestinal lumen. In addition, provided herein are methods and compositions for the treatment of developmental delay that reduce the total bile acid load in the serum by excreting bile acids in feces.

[0065] In children with chronic cholestasis, an additional consequence of childhood cholestasis and childhood cholestatic liver disease is decreased growth compared to children who do not have childhood cholestasis or childhood cholestatic liver disease. Accordingly, methods and compositions are provided herein for stimulating epithelial proliferation and/or regeneration of the intestinal mucosa and/or enhancing adaptive processes in the intestine in individuals (eg, children) with growth retardation. In some such embodiments, the methods involve increasing the concentration of bile acid in the intestinal lumen. Also provided herein are methods and compositions for the treatment of growth retardation by reducing the total bile acid load in the serum by excreting bile acids in the feces.

Progressive familial intrahepatic cholestasis (PFIC)

[0066] PFIC is a rare genetic disorder that causes progressive liver disease, typically leading to liver failure. In people with PFIC, liver cells are less able to produce bile. The resulting accumulation of bile causes liver disease in affected individuals. Signs and symptoms of PFIC typically begin in infancy. Patients experience severe itching, jaundice, an inability to grow at the expected rate (no growth), and an increasing inability 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 similarly characterized by impaired bile flow and progressive liver disease. PFIC 1

[0067] 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, encoding a P-type ATPase, is located on human chromosome 18 and also contains a mutation of the 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 mainly expressed in cholangiocytes. The P-type ATPase appears to be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine in the inner layer of the plasma membrane relative to the outer layer. 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 the secretion of bile acids by bile. Abnormal secretion of bile acids/salts leads to bile acid overload of hepatocytes.

[0068] PFIC 1 is typically present in infants (eg, 6-18 months of age). Infants may show signs of itchy skin, jaundice, bloating, diarrhea, malnutrition, and decreased growth. Biochemically, individuals with PFIC 1 are characterized by elevated serum transaminase, elevated bilirubin, elevated serum bile acids, and low gamma-GT. The individual may also have liver fibrosis. Individuals with PFIC 1 typically do not exhibit bile duct proliferation. Most individuals with PFIC 1 develop end-stage liver disease by age 10. No medications have been proven 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

[0069] PFIC 2 (also known as Byler syndrome, BSEP deficiency) is associated with mutations in the ABCB11 gene (also referred to as BSEP). The ABCB11 gene encodes the ATP-dependent tubular bile salt excretion 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 over extreme concentration gradients. Mutations in this protein are responsible for the reduced 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 damage.

[0070] PFIC 2 is typically present in infants (eg, 6-18 months of age). Infants may show signs of itchy skin. Biochemically, individuals with PFIC 2 are characterized by elevated serum transaminase, elevated bilirubin, elevated serum bile acids, and low gamma-GT. The individual may also have portal inflammation and giant cell hepatitis. In addition, individuals often develop hepatocellular carcinoma. No medications have been proven 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 poor growth). The PFIC 2 patient population represents approximately 60% of the total PFIC population.

PFIC 3

[0071] PFIC 3 (also known as MDR3 deficiency) is caused by a genetic defect in the ABCB4 gene (also called MDR3) located on chromosome 7. Class III multidrug-resistant P-glycoprotein (P-gp) (MDR3) is a phospholipid translocator , involved in the excretion of biliary phospholipid (phosphatidylcholine) through the canalicular membrane of the hepatocyte. PFIC 3 results from bile toxicity in which bile detergent salts are not inactivated by phospholipids, resulting in damage to the bile ducts and bile epithelium.

[0072] PFIC 3 is also present in early childhood. In contrast to PFIC 1 and PFIC 2, individuals have increased levels of gamma-GT. Individuals also experience portal inflammation, fibrosis, cirrhosis, and massive bile duct proliferation. Individuals may also develop intrahepatic cholelithiasis. Ursodiol was effective in treating or relieving PFIC 3. Benign recurrent intrahepatic cholestasis (BIC) BRIC 1

[0073] BRIC1 is caused by a genetic defect in the FIC1 protein in the canalicular membrane of hepatocytes. BRIC1 is generally associated with normal serum cholesterol and γ-glutamyl transpeptidase levels, but with elevated serum bile salts. Residual FIC1 expression and function are associated with BRIC1. Despite repeated bouts of cholestasis or cholestatic liver disease, most patients do not progress to chronic liver disease. During attacks, patients experience severe jaundice, itching, steatorrhea, and weight loss. Some patients also have kidney stones, pancreatitis and diabetes mellitus.BRIC2

[0074] BRIC2 is caused by mutations in ABCB11, which results in impaired expression and/or function of BSEP in the tubular membrane of hepatocytes.

BRIC3

[0075] BRIC3 is associated with defective expression and/or function of MDR3 in the canalicular membrane of hepatocytes. Patients with MDR3 deficiency typically have elevated serum gamma-glutamyl transpeptidase levels with normal or slightly elevated serum bile acid levels.

Dubin-Johnson syndrome (DJS)

[0076] DJS is characterized by conjugated hyperbilirubinemia due to inherited MRP2 dysfunction. In affected patients, liver function is preserved. Several different mutations are associated with this condition, resulting in either a complete absence of immunohistochemically detectable MRP2 in affected patients or impaired protein maturation and sorting.

Acquired cholestatic disease

Primary sclerosing cholangitis in pediatric patients (PSC)

[0077] PSC in children is a chronic inflammatory liver disease that slowly progresses to end-stage liver failure in most affected patients. In PSC from pediatric patients, inflammation, fibrosis, and obstruction of large and medium-sized intra- and extrahepatic ducts predominate.

Cholelithiasis

[0078] Gallstone disease is one of the most common and costly of all digestive system diseases, with a prevalence of up to 17% in Caucasian women. Cholesterol-containing gallstones are the main form of gallstones, so an oversaturation of bile with cholesterol is a prerequisite for the formation of gallstones. ABCB4 mutations may be involved in the pathogenesis of cholesterol gallstone disease. Drug-induced cholestasis

[0079] Inhibition of BSEP function by drugs is an important mechanism of drug-induced cholestasis leading to the accumulation of bile salts in the liver and subsequent damage to liver cells. Several drugs are involved in BSEP inhibition. Most of these drugs, such as rifampicin, cyclosporine, glibenclamide or troglitazone, directly inhibit ATP-dependent taurocholate transport in a competitive manner in cis, while estrogen and progesterone metabolites indirectly inhibit BSEP in trans after secretion into the bile duct by Mrp2. Alternatively, drug-mediated stimulation of MRP2 may contribute to cholestasis or cholestatic liver disease by altering bile composition.

General cholestasis associated with parenteral nutrition

[0080] 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 life. The degree of cholestasis or cholestatic liver disease and the chance of survival in these infants was 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 formulation, septic mediators are likely the largest contributors to changes in liver function.

Alagille syndrome

[0081] Alagille syndrome is a genetic disorder that affects the liver and other organs. It often appears in infancy (eg, 6–18 months of age) through early childhood (eg, 3–5 years of age) and may stabilize after age 10 years. Symptoms may include chronic progressive cholestasis, ductopenia, jaundice, pruritus, xanthomas, congenital heart problems, intrahepatic bile duct deficiency, 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 received ursodiol, hydroxyzine, cholestyramine, rifampicin and phenobarbitol. Because of the reduced ability to absorb fat-soluble vitamins, individuals with Alagille syndrome are additionally prescribed high-dose multivitamins. Biliary atresia.

[0082] Biliary atresia is a life-threatening condition in infants in which the bile ducts inside or outside the liver do not have normal openings. With biliary atresia, bile is retained, accumulates 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: intrauterine and perinatal. Fetal biliary atresia occurs while the baby is in the womb. Perinatal biliary atresia is much more common and does not appear until 2 weeks after birth.

Biliary atresia after the Kasai procedure

[0083] Biliary atresia is treated with a surgical procedure called the Kasai procedure or liver transplantation. The Kasai procedure is usually the first treatment for biliary atresia. During the Kasai procedure, a pediatric surgeon removes the baby's damaged bile ducts and lifts a loop of intestine to replace them. Although the Kasai procedure can restore the flow of bile 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 after successful surgery, most infants with biliary atresia slowly develop cirrhosis over the years and require a liver transplant by adulthood. Possible complications after the Kasai procedure include ascites, bacterial cholangitis, portal hypertension and pruritus.

Biliary atresia after liver transplantation

[0084] If the atresia is complete, liver transplantation is the only option. Although liver transplantation is generally successful in treating biliary atresia, liver transplantation can have complications such as organ rejection. A donor liver may also not be available. In addition, in some patients, liver transplantation may not be effective in treating biliary atresia.

Xanthoma

[0085] Xanthoma is a skin condition associated with cholestatic liver disease in which certain fats accumulate beneath the surface of the skin. Cholestasis results in several lipid disorders that result 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 normal removal of lipoprotein particles from the blood by the liver. General definitions

[0086] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs.

[0087] As used in this specification and the accompanying claims, the singular number includes the plural unless the context clearly dictates otherwise. Thus, for example, reference to “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 upon reading this disclosure.

[0088] As used herein, the term “baseline” or “pre-administration baseline” refers to information collected at the beginning of the study, or an initial known value that is used for comparison with later data. A baseline is an initial measurement of a measurable state that is taken at an early point in time and is used for comparison over time to look for changes in the measurable state. For example, the concentration of bile acids in the patient's blood 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 quality being measured, used for comparison with values that represent a response to an intervention or environmental exposure. Baseline represents time zero before study participants receive the experimental drug 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 the clinical trial or 2) the state of the measurand immediately before changing the dosage amount or composition administered to the patient from a first dosage amount or composition to a second dosage amount or compositions.

[0089] As used herein, the terms “content” and “concentration” are used interchangeably. For example, “high serum bilirubin” can alternatively be stated as “high serum bilirubin concentrations.”

[0090] As used herein, the terms “normalized” or “normal range” refer to age-specific values that are within the range corresponding to a healthy person (ie, normal or normalized values). For example, the phrase “serum bilirubin concentrations returned to normal within three weeks” means that serum bilirubin concentrations are within the range known in the art and consistent with that of a healthy person (i.e., within the normal range, not for example, in the range of elevated values) 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.

[0091] As used herein, the terms "ITCHRO(OBS)" and "ITCHRO" (alternatively, "ItchRO(Pt)") are used interchangeably with the qualification that the ITCHRO(OBS) score is used to measure the severity of itch in children under 18 years of age , and the ITCHRO scale is used to measure the severity of itching in adults over 18 years of age. Therefore, when the ITCHRO(OBS) score is mentioned in relation to an adult patient, the ITCHRO score is indicated as the scale. Likewise, whenever the ITCHRO score is mentioned in relation to a pediatric patient, the ITCHRO(OBS) score is typically reported (some older children were allowed to report their own scores as ITCHRO scores). The ITCHRO(OBS) scale ranges from 0 to 4 and the ITCHRO scale ranges from 0 to 10.

[0092] As used herein, the term “bile acid” or “bile acids” includes steroid acids (and/or their carboxylate anion) and salts thereof found in animal (e.g., human) bile, including, in as a 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 acid, 7-B-methylcholic acid, methyllithocholic acid, chenodeoxycholate, lithocholic acid, lithocholate, etc. 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. Therefore, the terms “bile acid,” “bile salt,” “bile acid/salt,” “bile acids,” “bile salts,” and “bile acids/salts,” unless otherwise noted, are used interchangeably herein. Any reference to a bile acid used herein includes a reference to a bile acid or a salt thereof. In addition, pharmaceutically acceptable bile acid esters are optionally used as the “bile acids” described herein, for example, bile acids/salts conjugated to an amino acid (eg, 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 to either glycine or taurine: glycocholate and taurocholate, respectively (and their salts). Any reference to a bile acid used herein includes a reference to the identical compound, whether produced naturally or synthetically. In addition, it should be understood that any reference in the singular to a component (bile acid or other) used herein includes reference to one and only one, one or more, or at least one of such components. Likewise, any multiple reference to a component used herein includes a reference to one and only one, one or more, or at least one of such components unless otherwise indicated.

[0093] The term “subject,” “patient,” “participant,” or “individual” is used interchangeably herein and refers to mammals and non-mammalian organisms, such as those suffering from the disorder described herein. Examples of mammals include, without limitation, any member of the class Mammals: humans, non-human primates such as chimpanzees, and other species of monkeys and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice, guinea pigs, etc. 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.

[0094] As used herein, the term “about” includes any value that is within 10% of the described value.

[0095] As used herein, the term “composition” includes both the composition and the composition administered in the manner described herein. Additionally, in some embodiments, the composition of the present invention is or includes a “formulation,” an oral dosage form, or a rectal dosage form, as described herein.

[0096] The terms “treat” or “treatment” and other grammatical equivalents as used herein include alleviation, suppression or reduction of symptoms, reduction or suppression of severity, reduction in frequency, reduction or suppression of relapse, delay of onset, delay of relapse, reducing or alleviating symptoms of a disease or condition, eliminating the 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 stopping symptoms of a disease or condition. These terms also include the achievement of a therapeutic effect. By therapeutic effect is meant the elimination or improvement of the underlying disorder being treated and/or the elimination or improvement of one or more physiological symptoms associated with the underlying disorder such that the patient experiences an improvement.

[0097] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of at least one agent administered (e.g., a therapeutically active agent) that achieves a desired result in a subject or individual, for example, to relieve to some extent one or more symptoms of the disease or condition being treated. In some cases, the result is a reduction and/or alleviation of signs, symptoms or causes of 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 specified herein necessary to provide a clinically significant reduction in disease. The appropriate "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 ASBTI refers to a sufficient amount of ASBTI to treat cholestasis or cholestatic liver disease in a subject or individual.

[0098] As used herein, the terms “introduce,” “introducing,” and the like.

refer to methods that can be used to ensure 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. Methods of administration that are optionally used with the agents and methods described herein can be found in sources, for example, Goodman and Gilman, 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 entirety for all purposes. In some embodiments, the agents and compositions described herein are administered orally.

[0099] 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).

[00100] 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 cause adverse reactions when administered to a mammal (eg, 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 Pharmacopoeia or other generally accepted pharmacopoeia for use in mammals and, more particularly, in humans.

[00101] In various embodiments, pharmaceutically acceptable salts described herein include, by way of non-limiting example, 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. In addition, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium) , alkali metal salts (for example, sodium-dependent or potassium), ammonium salts, etc.

Bile acid

[00102] Bile contains water, electrolytes, and a variety of organic molecules, including bile acids, cholesterol, phospholipids, and bilirubin. Bile is secreted from the liver and accumulates in the gallbladder, and when the gallbladder contracts due to ingestion of fatty foods, the bile passes through the bile duct into the intestine. Bile acids/salts are critical for the digestion and absorption of fats and fat-soluble vitamins in the small intestine. Adults produce 400 to 800 ml of bile daily. It can be considered that the secretion of bile occurs in two stages. Initially, hepatocytes secrete bile into canaliculi from which it flows into the bile ducts, and this hepatic bile contains large amounts of bile acids, cholesterol and other organic molecules. Then, as the bile flows through the bile ducts, it is modified by the addition of watery, bicarbonate-rich secretions from the ductal epithelial cells. During storage in the gallbladder, bile is concentrated, as a rule, five times.

[00103] Bile flow is lowest during fasting and most of the bile is diverted to the gallbladder for concentration. When chyme from ingested food enters the small intestine, acids and partially digested fats and proteins stimulate the secretion of cholecystokinin and secretin, which are important for the secretion and flow of bile. Cholecystokinin (cholecysto = gallbladder and kinin = movement) is a hormone that stimulates the contraction of the gallbladder and common bile duct, resulting in the delivery of bile to the intestines. The most powerful 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 bile duct cells that produce bicarbonate and water, which increases the volume of bile and increases its flow into the intestines.

[00104] Bile acids/salts are derivatives of cholesterol. Cholesterol that enters the body with food or obtained as a result of synthesis in the liver is converted into bile acids/salts in hepatocytes. Examples of such bile acids/salts include cholic and chenodeoxycholic acids, 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 abundant bile salts in humans are cholate and deoxycholate, and they are typically conjugated to either glycine or taurine to form glycocholate or taurocholate, respectively.

[00105] Free cholesterol is practically 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, secretion into bile is the main route of cholesterol excretion. Large amounts of bile acids/salts are secreted into the intestines every 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 absorbed back into the blood in the ileum through a process known as “enterohepatic recirculation.”

[00106] Venous blood from the ileum goes directly into the portal vein and therefore through the liver sinusoids. Hepatocytes are very efficient at extracting bile acids/salts from sinusoidal blood, and a small portion of them passes 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 recycled approximately 20 times, often two or three times during a single digestive phase. Bile biosynthesis represents 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. In 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 through bile salt recycling. 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 dietary lipids and returned to the liver for reuse. Thus, processing allows the daily secretion of 20-30 g of bile salts into the small intestine.

[00107] 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 typically 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 an aqueous environment. Bile acids/salts have a detergent effect on dietary fat particles, resulting in the destruction or emulsification of fat globules. Emulsification is important because it significantly increases the surface area of the fat available for digestion by lipases that cannot get inside the lipid droplets. In addition, bile acids/salts are lipid carriers and are capable of solubilizing many lipids to form micelles and are critical for the transport and absorption of fat-soluble vitamins.

[00108] As used herein, the term “non-systemic” or “minimally absorbed” refers to the low systemic bioavailability and/or absorption of the administered compound. In some embodiments, a non-systemic compound is a compound that is not substantially absorbed systemically. In some embodiments, the ASBTI compositions described herein deliver ASBTI to the distal ileum, colon, and/or rectum rather than systemically (eg, 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, systemic absorption of the non-systemic compound is <10% of the administered dose. In some embodiments, systemic absorption of the non-systemic compound is <15% of the administered dose. In some embodiments, systemic absorption of the non-systemic compound is <25% of the administered dose. In an alternative approach, non-systemic ASBTI is a compound that has lower systemic bioavailability compared to the systemic bioavailability of systemic ASBTI (eg, compounds 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 systemic ASBTI (eg, compounds 100A, 100C).

[00109] 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 an administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <30% of an administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <40% of an administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <50% of an administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <60% of an administered dose of ASBTI. In some embodiments, the compositions described herein are formulated to systemically deliver <70% of an 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, and the like.

[00110] The term "optionally substituted" or "substituted" means that the specified group is replaced by one or more additional groups. In some embodiments, 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, arylsulfoxide , ester, alkylsulfone, arylsulfone, cyano-, halogen, alkyl, alkoyloxo-, isocyanato-, thiocyanato-, isothiocyanato-, nitro-, haloalkyl, haloalkoxy-, fluoroalkyl, amino-, alkylamino-, dialkylamino-, amido-groups.

[00111] 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, t-butyl, pentyl, isopentyl, neopentyl and hexyl. In some embodiments, alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary 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 (eg, a CH ₂ group to an NH group or an O group).

[00112] The term "alkylene" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be an 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 a C ₁ -C ₆ alkylene. Typical alkylene groups include, but are not limited to, -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )-, - CH ₂ CH (CH ₃ ) ₂ -, -CH ₂ CH ₂ CH _{2 -} , -CH ₂ CH 2 CH 2 CH ₂ -, -CH ₂ CH ₂ CH ₂ CH _{2 CH 2} -, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - etc.

[00113] The group "alkoxy" refers to an (alkyl)O-group, where alkyl is as defined herein.

[00114] The term "alkylamine" refers to the group -N(alkyl) _x H _y , where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y= O. When x=2, alkyl groups taken together with the nitrogen to which they are attached do not necessarily form a cyclic ring system.

[00115] "Amide" is a chemical moiety with the formula -C(O)NHR or -NHC(O)R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon) and heteroalicyclic group (linked through a carbon rings).

[00116] The term “ester” refers to a chemical moiety of the formula C(=O)OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl and heterooalicyclic.

[00117] 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.

[00118] The term "aromatic" refers to a planar ring having a delocalized π electron system containing 4n+2π: electrons, where n is an integer. Aromatic rings may consist 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", eg phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (eg pyridine). The term includes monocyclic or polycyclic fused ring groups (ie, rings that share adjacent pairs of carbon atoms).

[00119] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical where each of the atoms forming the ring (ie, the backbone atoms) is a carbon atom. In various embodiments, the cycloalkyls are saturated or partially unsaturated. In some embodiments, the cycloalkyls are fused to an aromatic ring. Cycloalkyl groups include groups containing from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following:

[00120] and the like. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[00121] The term "heterocyclo" refers to heteroaromatic and

heteroalicyclic groups containing from 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 the specified 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 (azetidine derivative). 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, il, oxepanil, tiepanil, oxazepinil, diazepinil, thiazepinil, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrotiranyl, 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, silt, phthalazinil , pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl.

[00122] 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, the heteroaryl groups are monocyclic or polycyclic. Illustrative examples of heteroaryl groups include the following:

and so on.

[00123] 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 called non-aromatic heterocycles, include:

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

[00124] The term "halo" or alternatively "halogen" means fluorine, chlorine, bromine and iodine.

[00125] The terms “haloalkyl” and “haloalkoxy” include alkyl and alkoxy structures that are substituted with one or more halogens. In embodiments where more than one halogen is included in a 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.

[00126] 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, but are not limited to, -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ - CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . In some embodiments, up to two heteroatoms are consecutive, such as -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si(CH ₃ ) ₃ .

[00127] The "cyano" group refers to the -CN group.

[00128] The "isocyanato" group refers to the -NCO group.

[00129] The "thiocyanato" group refers to the -CNS group.

[00130] The group "isothiocyanato" refers to the -NCS group.

[00131] "Alcoyloxy" refers to the group RC(=O)O-.

[00132] "Alcoyl" refers to the group RC(=O)-.

[00133] As used herein, the term “modulate” refers to some influence (eg, increasing, enhancing, or maintaining a certain level).

[00134] The term "optionally substituted" or "substituted" means that the specified group may be substituted by one or more additional groups individually and independently selected from C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, aryl, heteroaryl, C ₂ -C ₆ -heteroalicyclic group, hydroxy, C ₁ -C ₆ -alkoxy, aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy, C ₁ -C ₆ -alkylthio, aryltio, C ₁ -C ₆ -alkyl sulfoxide, aryl sulfoxide, C ₁ - C ₆ -alkylsulfone, arylsulfone, cyano, halogen, C ₂ -C ₈ -acyl, C ₂ -C ₈ -acyloxy, nitro, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -fluoroalkyl and amino, including C ₁ -C ₆ -alkylamino and their protected derivatives. By way of example, optional substituents may be L ^s R ^s , where each L ^s is independently selected from the bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O ) ₂ -, -NH-, -NHC(=O)-, -C(=O)NH-, S(=O) ₂ NH-, -NHS(=O) ₂ -, -OC(=O)NH -, -NHC(=O)O-, -(C ₁ -C ₆ -alkyl)- or -(C ₂ -C ₆ -alkenyl)-; and each R ^s is independently selected from H, (C ₁ -C ₄ -alkyl), (C ₃ -C ₈ -cycloalkyl), heteroaryl, aryl and C ₁ -C ₆ -heteroalkyl. Optionally substituted non-aromatic groups may be substituted by 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, which is bonded to two adjacent carbon atoms (ie, forming an epoxide).

ASBT inhibitors

[00135] In various embodiments of the methods of the present invention, ASBT inhibitors are administered to a subject. ASBT inhibitors (ASBTIs) reduce or inhibit the recirculation of bile acids in the distal gastrointestinal (GI) tract, including the distal ileum, colon and/or rectum. Inhibition of apical sodium-dependent bile acid transport interrupts the enterohepatic circulation of bile acids and results in more bile acids being excreted in the feces, see FIG. 1, which results in a systemic decrease in bile acids, thereby reducing bile acid-mediated liver damage and associated effects and complications. In some embodiments, the ASBTIs are absorbed systemically. In some embodiments, ASBTIs are not systemically absorbed. In some embodiments, the ASBTIs described herein are modified or replaced (eg, by the group -L-K) to be non-systemic. In some embodiments, any ASBT inhibitor is modified or substituted with one or more charged groups (eg, K) and optionally one or more linkers (eg, L), where L and K are as defined herein.

[00136] In some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula I:

[00137]

[00138] where:

[00139] R ¹ represents a C _1-6 straight chain alkyl group;

[00140] R ² represents a C _1-6 straight chain alkyl group;

[00141] R ³ represents hydrogen or an OR ¹¹ group in which R ¹¹ represents hydrogen, optionally substituted with a C _1-6 alkyl or a C _1-6 alkylcarbonyl group;

[00142] R ⁴ is pyridyl or optionally substituted phenyl or -L _z -K _z ; where z is 1, 2 or 3; each L independently represents a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl l; each K represents a group that prevents systemic absorption;

[00143] R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and each is 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 ) _p NR ¹² R ¹³ , O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ and WR ³¹ , where W represents O or NH and R ³¹ is selected from

[00144]

[00145] 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

[00146] R ⁶ and R ⁷ are associated with the formation of a group

[00147]

[00148] where R ¹² and R ¹³ are characterized by the values specified above, am is equal to 1 or 2; and

[00149] R ⁹ and R ¹⁰ are the same or different, and each is selected from hydrogen or C _1-6 alkyl; and

[00150] its salts, solvates and physiologically functional derivatives.

[00151] In some embodiments of the methods described herein, a compound of Formula I is a compound,

[00152] in which

[00153] R ¹ represents a C _1-6 straight chain alkyl group;

[00154] R ² represents a C _1-6 straight chain alkyl group;

[00155] R ³ represents hydrogen or an OR ¹¹ group, in which R ¹¹ represents hydrogen, optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00156] R ⁴ is optionally substituted phenyl;

[00157] R ⁵ , R ⁶ and R ⁸ are independently selected from hydrogen, C _1-4 alkyl, optionally substituted with fluorine, C _1-4 alkoxy, halogen or hydroxy;

[00158] 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 ;

[00159] where n, p and R ¹² -R ¹⁵ are characterized by the above values;

[00160] provided that at least two of R ⁵ -R ⁸ are not hydrogen; and

[00161] salt solvates and physiologically functional derivatives thereof.

[00162] In some embodiments of the methods described herein, a compound of Formula I is a compound,

[00163] in which

[00164] R ¹ represents a C _1-6 straight chain alkyl group;

[00165] R ² represents a C _1-6 straight chain alkyl group;

[00166] R ³ represents hydrogen or an OR ¹¹ group in which R ¹¹ represents hydrogen, optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00167] R ⁴ is unsubstituted phenyl;

[00168] R ⁵ represents hydrogen or halogen;

[00169] R ⁶ and R ⁸ are independently selected from hydrogen, C _1-4 alkyl, optionally substituted with fluorine, C _1-4 alkoxy, halogen or hydroxy;

[00170] R ⁷ 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)nR ¹⁵ , O(CH ₂ ) _p SO ₃ R ¹⁵ , O(CH ₂ )NR ¹² R ¹³ and O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ , where p represents an integer from 1 to 4, n represents 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;

[00171] R ⁹ and R ¹⁰ are the same or different, and each is selected from hydrogen or C _1-6 alkyl; and

[00172] its salts, solvates and physiologically functional derivatives.

[00173] According to some embodiments of the methods in which the compound of Formula I is a compound,

[00174] in which

[00175] R ¹ is methyl, ethyl or n-propyl;

[00176] R ² is methyl, ethyl, n-propyl, n-butyl or n-pentyl;

[00177] R ³ represents hydrogen or an OR ¹¹ group, where R ¹¹ represents hydrogen, optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00178] R ⁴ is unsubstituted phenyl;

[00179] R ⁵ is hydrogen;

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

[00181] R ⁷ 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)nR ¹⁵ , O(CH ₂ ) _p SO ₃ R ¹⁵ , O(CH ₂ )NR ¹² R ¹³ and O(CH ₂ ) _p N ⁺ R ¹² R ¹³ R ¹⁴ , where p represents an integer from 1 to 4, n represents 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;

[00182] R ⁹ and R ¹⁰ are the same or different, and each is selected from hydrogen or C _1-6 alkyl; and its salts, solvates and physiologically functional derivatives.

[00183] In some embodiments of the methods, a compound of Formula I is a compound

[00184] in which

[00185] R ¹ is methyl, ethyl or n-propyl;

[00186] R ² is methyl, ethyl, n-propyl, n-butyl or n-pentyl;

[00187] R ³ represents hydrogen or an OR ¹¹ group, where R ¹¹ represents hydrogen, optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00188] R ⁴ is unsubstituted phenyl;

[00189] R ⁵ represents hydrogen;

[00190] R ⁶ is C _1-4 alkoxy, halogen or hydroxy;

[00191] R ⁷ represents OR ¹⁵ where R ¹⁵ represents hydrogen or optionally substituted C _1-6 -alkyl;

[00192] R ⁸ is hydrogen or halogen;

[00193] R ⁹ and R ¹⁰ are the same or different, and each is selected from hydrogen or C _1-6 alkyl; and its salts, solvates and physiologically functional derivatives.

[00194] In 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-benzothiazepin-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-benzothiazepin-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-benzothiaxepin-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-benzothiazepin-7-ol-1,1-dioxide; (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-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-benzothiazepin-4-ol-1,1-dioxide; (±)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-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-ylhydrosulfate or 3,3-diethyl- 2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrosulfate.

[00195] In some embodiments, a compound of Formula I is

or

[00196] In some embodiments of the methods, the compound of Formula I is

[00197] In some embodiments, the compound of Formula I is not the structure shown as:

[00198] where m is an integer from 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.

[00199] In some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula II.

[00200] where:

[00201] q is an integer from 1 to 4;

[00202] n is an integer from 0 to 2;

[00203] 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,

[00204] 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 ,

[00205] where 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,

[00206] wherein 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

[00207] R ¹ and R ² taken together with the carbon atom to which they are attached form C ₃ -C ₁₀ -cycloalkyl;

[00208] 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 where R ⁹ and R ¹⁰ are as defined above; or

[00209] R ³ and R ⁴ together represent =O, =NOR ¹¹ , =S, =NNR ¹¹ R ¹² , =NR ⁹ or =CR ¹¹ R ¹² .

[00210] where 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 , where R ⁹ and R ¹⁰ are characterized by the values specified above, provided that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00211] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00212] 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 ;

[00213] where z is 1, 2 or 3; each L independently represents a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl l; each K represents a group that prevents systemic absorption;

[00214] where 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 ^- ,

[00215] where:

[00216] 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 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

[00217] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may optionally have one or more carbon atoms 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, and 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, quaternary heteroarylalkyl and GTVW,

[00218] wherein 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

[00219] 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

[00220] W is a quaternary heterocycle, quaternary heteroaryl, 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

[00221] 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,

[00222] where R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M;

or

[00223] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and

[00224] selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl and arylalkyl; and

[00225] R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; and

[00226] one or more R ^x is 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 acid, peptide, polypeptide and carbohydrate,

[00227] 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

[00228] where R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

[00229] wherein 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,

[00230] where 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, amino acid, peptide, polypeptide, carbohydrate, polyether or polyalkyl,

[00231] wherein 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 ;

[00232] wherein the 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 , 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 , NO2, 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 ^- ,

[00233] with the proviso that both R ⁵ and R ⁶ cannot represent hydrogen or SH;

[00234] with the proviso that when R ⁵ or R ⁶ is phenyl, only one of R ¹ or R ² is H;

[00235] with the proviso 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.

[00236] In some embodiments of the methods, a compound of Formula II is a compound wherein

[00237] q is an integer from 1 to 4;

[00238] n is 2;

[00239] R ¹ and R ² are independently selected from the group consisting of H, alkyl, alkoxy, dialkylamino and alkylthio,

[00240] 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 ;

[00241] each R ⁹ and R ¹⁰ are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, acyl, heterocycle and arylalkyl;

[00242] 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 , where R ⁹ and R ¹⁰ are as defined above;

[00243] 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 , where R ⁹ and R ¹⁰ are characterized by the values specified above, provided that that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00244] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00245] R ⁵ and R ⁶ are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, heterocycle and -L _z -K _z ;

[00246] where z is 1 or 2; each L independently represents 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 represents a group that prevents systemic absorption;

[00247] 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 ,

[00248] where:

[00249] A ^is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation;

[00250] 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, where 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

[00251] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and

[00252] selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl and arylalkyl; and

[00253] R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; and

[00254] one or more R ^x is 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 ;

[00255] with the proviso that both R ⁵ and R ⁶ may not be hydrogen;

[00256] with the proviso that when R ⁵ or R ⁶ is phenyl, only one of R ¹ or R ² is H;

[00257] with the proviso 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.

[00258] In some embodiments, a compound of Formula II is a compound in which

[00259] q is 1;

[00260] n is 2;

[00261] R ^x is N(CH ₃ ) ₂ ;

[00262] R ⁷ and R ⁸ independently represent H;

[00263] R ¹ and R ² are alkyl;

[00264] R ³ is H and R ⁴ is OH;

[00265] 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 ;

[00266] where z is 1, 2 or 3; each L independently represents a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted aminoalkyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl l; each K represents a group that prevents systemic absorption;

[00267] 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 ^- ,

[00268] 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

[00269] 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, and R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of from hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl and -GTVW,

[00270] 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

[00271] G, T and V each independently represent 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 substituted carboalkoxyalkyl or substituted or unsubstituted cycloalkyl, and

[00272] W is a quaternary heterocycle, quaternary heteroaryl, 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

[00273] 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;

[00274] 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 , where R ⁹ and R ¹⁰ are characterized by the values specified above, provided that that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00275] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00276] 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,

[00277] where R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M; or

[00278] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl and arylalkyl;

[00279] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00280] In some embodiments, a compound of Formula II is a compound in which

[00281] q is 1;

[00282] n is 2;

[00283] R ^x is N(CH ₃ ) ₂ ;

[00284] R ⁷ and R ⁸ independently represent H;

[00285] R ¹ and R ² independently represent C ₁ -C ₄ -alkyl;

[00286] R ³ is H and R ⁴ is OH;

[00287] 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 ^- ,

[00288] 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

[00289] 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, and R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of from hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, quaternary heteroarylalkyl and GTVW,

[00290] 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

[00291] 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

[00292] W is a quaternary heterocycle, quaternary heteroaryl, 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

[00293] 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;

[00294] 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 , where R ⁹ and R ¹⁰ are characterized by the values specified above, provided that that both R ³ and R ⁴ cannot be OH, NH ₂ and SH, or

[00295] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring;

[00296] 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,

[00297] where R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M; or

[00298] R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; and selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl and arylalkyl;

[00299] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00300] In some embodiments of the methods, a compound of formula II is a compound,

[00301] in which

[00302] R ⁵ and R ⁶ are independently selected from the group consisting of H, aryl, heterocycle, quaternary heterocycle and quaternary heteroaryl.

[00303] 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 , NO2, 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 .

[00304] In some embodiments of the methods, a compound of Formula II is a compound

[00305] in which

[00306] R ⁵ or R ⁶ is -Ar-(R ^y ) _t

[00307] t is an integer from 0 to 5;

[00308] 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

[00309] one or more R ^y is 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 ;

[00310] wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle may be further substituted by 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;

[00311] 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.

[00312] In some embodiments of the methods, a compound of Formula II is a compound in which

[00313] R ⁵ or R ⁶ is

[00314]

[00315] In some embodiments of the methods, a compound of Formula II is a compound wherein n is 1 or 2. In some embodiments of the methods, a compound of Formula II is a compound in which R ¹ and R ² are independently H or C _{1- 7} -alkyl. In some embodiments of the methods, a compound of Formula II is a compound in which each C _1-7 alkyl is independently ethyl, n-propyl, n-butyl, or isobutyl. In some embodiments of the methods, a 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/

[00316] In some embodiments of the methods, a compound of Formula II is a compound in which one or more R ^x is at the 7, 8, or 9 position 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 the 7-position of the benzene ring of Formula II. In some embodiments of the methods, a compound of Formula II is a compound wherein one or more R ^x is independently selected from OR ¹³ and NR ¹³ R ¹⁴ .

[00317] In some embodiments of the methods, a compound of Formula II is a compound

[00318] in which:

[00319] q is 1 or 2;

[00320] n is 2;

[00321] R ¹ and R ² are each alkyl;

[00322] R ³ is hydroxy;

[00323] R ⁴ and R ⁶ are hydrogen;

[00324] R ⁵ is characterized by the formula

[00325]

[00326] where

[00327] t is an integer from 0 to 5;

[00328] one or more RYs are OR ¹³ or OR ¹³ R ¹⁴ ;

[00329] 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;

[00330] 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, carbohydrate, amino acid, peptide or polypeptide;

[00331] 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, 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,

[00332] where A is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,

[00333] 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;

[00334] 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 , where R ⁹ and R ¹⁰ are characterized by the values specified above, provided that that both R ³ and R ⁴ cannot represent OH, NH ₂ and SH; or

[00335] R ¹¹ and R ¹² together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and

[00336] R ¹⁶ and R ¹⁷ are independently selected from the substituents comprising R ⁹ and M;

[00337] R ⁷ and R ⁸ are hydrogen; and

[00338] one or more R ^x is independently selected from the group consisting of alkoxy, alkylamino and dialkylamino, and -WR ³¹ where W is O or NH and R ³¹ is selected from

And

[00339] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[00340] In some embodiments, a compound of Formula II is ,

or or the like

[00341] In some embodiments of the methods, the compound of Formula II is

[00342]

[00343] In certain embodiments, ASBTIs suitable for the methods described herein are non-systemic analogues of compound 100C. Certain compounds presented herein are analogues of compound 100C, modified or substituted to include a charged group. In certain embodiments, the analogues of compound 100C are modified or replaced with a charged group that is an ammonium group (eg, a cyclic or acyclic ammonium group). In some embodiments, the ammonium group is a non-protic ammonium group that contains quaternary nitrogen.

[00344] In some embodiments, a compound of Formula II is

[00345]

[00346] In 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-benzothipin-5yl]phenyl]amino]-5-oxopentyl]amino]-1-deoxy-D-glucitol or SA HMR1741 (also known as BARI -1741).

[00347] In some embodiments, a compound of Formula II is

[00348]

[00349] In some embodiments, the compound of Formula II is potassium ((2R,R3,4S,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).

[00350] In some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula III:

[00351]

[00352] where:

[00353] each R ¹ , R ² independently represents 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 alkylheterocycloal keel or LK; or R ¹ and R ² together with the nitrogen to which they are attached form a 3-8 membered ring which is optionally substituted with R ⁸ ;

[00354] each R ³ , R ⁴ independently represents 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 alkylheterocycloal keel or LK;

[00355] 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,

[00356] each R ⁶ , R ⁷ independently represents 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 alkylheterocycloal keel or LK; or R ⁶ and R ⁷ taken together form a bond;

[00357] each X is independently NH, S or O;

[00358] each Y is independently NH, S or O;

[00359] 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 substituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl or -LK;

[00360] L is _An , wherein

[00361] 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; where each m is independently equal to 0-2;

[00362] n is 0-7;

[00363] K represents a group that prevents systemic absorption;

[00364] with the proviso that at least one of R ¹ , R ² , R ³ or R ⁴ is -LK;

[00365] or a pharmaceutically acceptable prodrug thereof.

[00366] In some embodiments, the compounds of Formula III, R ¹ and R ³ are -LK. In some embodiments, R ¹ , R ² and R ³ are LK.

[00367] In some embodiments, at least one of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , and ^R7 is H. In some embodiments, ^R5 , ^R6 , ^R7 is H, and R ¹ , R ² , R ³ and R ⁴ represent 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.

[00368] 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 an 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.

[00369] In some embodiments, L is C ₁ -C ₇ alkyl. In some embodiments, L is heteroalkyl. In some embodiments, L is a C ₁ -C ₇ -alkylaryl. In some embodiments, L is C ₁ -C ₇ -alkylaryl-C ₁ -C ₇ -alkyl.

[00370] 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 nonprotic ammonium group. In some embodiments, each K is an acyclic nonprotic ammonium group.

[00371] In certain embodiments, each K is a cyclic nonprotic ammonium group of the structure:

[00372] In certain embodiments, K is an acyclic nonprotic ammonium group of the structure:

[00373] where p, q, R ⁹ , R ¹⁰ and Z are characterized by the values specified above. In some embodiments, p is 1. In other embodiments, p is 2. In additional embodiments, p is 3. In some embodiments, q is 0. In other embodiments, q is 1. In some other embodiments, q is 2.

[00374] The compounds further contain 1, 2, 3 or 4 anionic counterions selected from Cl ^- , Br ^- , I ^- , R ¹¹ SO ₃ ^- , (SO ₃ ^- -R ¹¹ -SO ₃ ^- ), R ¹¹ CO ₂ ^- , (CO ₂ ^- -R ¹¹ -CO ₂ ^- ), (R ¹¹ ) ₂ (P=O)O ^- and (R ¹¹ )(P=O)O ₂ ^2- , where R ¹¹ is as defined higher. In some embodiments, the counterion is Cl ^- , Br ^- , I ^- , CH ₂ CO ₂ ^- , CH ₃ SO ₃ ^- , or C ₆ H ₅ SO ₃ ^- or CO ₂ ^- - (CH ₂ ) ₂ -CO ₂ ^- . In some embodiments, a compound of Formula III contains one K group and one counterion. In other embodiments, the Formula III compound contains one K group and two molecules of the Formula III compound contain one counterion. In still other embodiments, a compound of Formula III contains two K groups and two counterions. In some other embodiments, a compound of Formula III contains one K group containing two ammonium groups and two counterions.

[00375] Also described herein are compounds characterized by Formula IIIA:

[00376] where:

[00377] each R ¹ , R ² independently represents 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 which is optionally substituted with R ⁸ ;

[00378] and R ³ , R ⁴ , R ⁸ , L and K are characterized by the values specified above.

[00379] In some embodiments of compounds of Formula IIIA, L is _An , wherein each A is a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl, and n is 0-7. In certain specific embodiments of the Formula IIIA compound, R ¹ is H. In certain 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.

[00380] Also described herein are compounds characterized by Formula IIIB:

[00381] where:

[00382] each R ³ , R ⁴ independently represents H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl or LK;

[00383] and R ¹ , R ² , L and K are characterized by the values specified above.

[00384] In certain embodiments of Formula IIIB, R ³ is H. In certain embodiments, R ³ and R ⁴ 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.

[00385] In some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula IIIC.

[00386]

[00387] where:

[00388] each R ¹ , R ² independently represents 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 alkylheterocycloal keel or LK; or R ¹ and R ² together with the nitrogen to which they are attached form a 3-8 membered ring which is optionally substituted with R ⁸ ;

[00389] each R ³ , R ⁴ independently represents 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 alkylheterocycloal kil or -LK;

[00390] 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,

[00391] each R ⁶ , R ⁷ independently represents 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 alkylheterocycloal kil or -LK; or R ⁶ and R ⁷ taken together form a bond;

[00392] each X is independently NH, S or O;

[00393] each Y is independently NH, S or O;

[00394] 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 substituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkylheterocycloalkyl or LK;

[00395] L is _An , wherein

[00396] each A independently represents 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; where each m is independently equal to 0-2;

[00397] n is 0-7;

[00398] K represents a group that prevents systemic absorption;

[00399] or a pharmaceutically acceptable salt thereof.

[00400] In certain specific embodiments of Formula I, II, or III, K is selected from

And

[00401]

[00402] In some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula IV:

[00403]

[00404] where

[00405] R ¹ represents a C _1-6 straight chain alkyl group;

[00406] R ² represents a C _1-6 straight chain alkyl group;

[00407] R ³ represents hydrogen or an OR ¹¹ group, where R ¹¹ represents hydrogen, optionally substituted with a C _1-6 alkyl or C _1-6 alkylcarbonyl group;

[00408] R ⁴ is pyridyl or optionally substituted phenyl;

[00409] R ⁵ , R ⁶ and R ⁸ are the same or different, and each is selected from:

[00410] 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 )PCN, CONR ¹² R ¹³ , (CH ₂ )PCO ₂ R ¹⁵ , (CH ₂ )PNR 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

[00411] p is an integer from 1 to 4,

[00412] n is an integer from 0 to 3 and

[00413] R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from hydrogen and optionally substituted C _1-6 alkyl;

[00414] R ⁷ is a group of the formula

[00415]

[00416] or

[00417]

[00418] where hydroxyl groups may be replaced by acetyl, benzyl,

[00419] or -(C ₁ -C ₆ )-alkyl-R ¹⁷ ,

[00420] wherein the alkyl group may be replaced by one or more hydroxyl groups;

[00421] R ¹⁶ is -COOH, -CH ₂ -OH, -CH ₂ -O-acetyl, -COOME or -COOEt;

[00422] R ¹⁷ is H, -OH, -NH ₂ , COOH or COOR ¹⁸ ;

[00423] R ¹⁸ is (C ₁ -C ₄ )-alkyl or -NH-(C ₁ -C ₄ )-alkyl;

[00424] X is -NH- or -O-; and

[00425] R ⁹ and R ¹⁰ are the same or different, and each represents hydrogen or C ₁ -C ₆ -alkyl; and its salts.

[00426] In some embodiments, a Formula IV compound has a Formula IVA or Formula IVB form structure:

[00427]

[00428]

[00429] In some embodiments, a compound of Formula IV has a structure of formula IVC:

[00430]

[00431] In some embodiments of Formula IV, X is O and R ⁷ is selected from

[00432] or

[00433] In some embodiments, the compound of Formula IV is:

[00434]

[00435] In some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula V:

[00436]

[00437]

[00438] where:

[00439] R ^v is selected from hydrogen or C _1-6 -alkyl;

[00440] 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;

[00441] 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;

[00442] 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;

[00443] n is 0-5;

[00444] one of R ⁴ and R ⁵ is a group of formula (VA):

[00445]

[00446] 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 _1-6 -alkenyl, C _1-6 -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;

[00447] wherein R ³ and R ⁶ and the other of R ⁴ and R ⁵ may be optionally substituted on the carbon atom by one or more R ¹⁷ ;

[00448] X is -O-, -N(R ^a )-, -S(O) _b - or -CH(R ^a )-

[00449] where R ^a represents hydrogen or C _1-6 -alkyl, ab is equal to 0-2;

[00450] Ring A is aryl or heteroaryl;

[00451] wherein ring A is optionally substituted on the carbon atom with one or more substituents selected from R ¹⁸ ;

[00452] R ⁷ is hydrogen, C _1-6 alkyl, carbocyclyl or heterocyclyl;

[00453] wherein R ⁷ is optionally substituted on the carbon atom with one or more substituents selected from R ¹⁹ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ²⁰ ;

[00454] R ⁸ is hydrogen or C _1-6 alkyl;

[00455] R ⁹ represents hydrogen or C _1-6 -alkyl;

[00456] R ¹⁰ is hydrogen, halogen, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulfamoyl, hydroxyaminocarbonyl, C _1-10 alkyl, C _1-10 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) ₂ -ammonio, C _1-10 -alkanoylamino, N-(C _1-10 -alkyl)carbamoyl, N,N-(C _1-10 -alkyl-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 -alkoxycarboxylamino, 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 the carbon atom by one or more substituents selected from R ²³ ; and where, if said heterocyclyl contains a -NH- group, this nitrogen may be optionally substituted by a group selected from R ²⁴ ; or R ¹⁰ represents a group of formula (VB):

[00457]

[00458] where:

[00459] R ¹¹ is hydrogen or C _1-6 alkyl;

[00460] 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 ranges 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 be independently and optionally substituted on the carbon atom with one or more substituents selected from R ²⁵ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ²⁶ ;

[00461] 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 ranges 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) ₂ - or heterocyclyl(C _{1- 10} -alkylene) _r -R ²⁸ - (C _1-10 -alkylene) _s -; where R ¹⁴ is optionally substituted on the carbon atom with one or more substituents selected from R ²⁹ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ³⁰ ; or R ¹⁴ represents a group of formula (VC):

[00462]

[00463] R ¹⁵ is hydrogen or C _1-6 alkyl; and R ¹⁶ represents hydrogen or C _1-6 -alkyl; where R ¹⁶ may be optionally substituted on the carbon atom by one or more groups selected from R ³¹ ;

[00464] or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl may be optionally substituted on the carbon atom by one or more R ³⁷ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ³⁸ ;

[00465] m is 13; and the values of R ⁷ may be the same or different;

[00466] 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 and optionally substituted on a carbon atom by one or more R ³⁴ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ³⁵ ;

[00467] 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 -; where R ³⁶ is selected from hydrogen or C _1-6 -alkyl, and x is equal to 0-2;

[00468] p, q, r and s are independently selected from 0-2;

[00469] 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, methyl ulfinyl, mesyl, N-methyl sulfamoyl, N,N-dimethylsulfamoyl, N-methylsulfamoylamino and N,N-dimethylsulfamoylamino;

[00470] 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

[00471] 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, and heteroaryl may, unless otherwise specified, be linked with carbon or nitrogen;

[00472] 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, and heterocyclyl may, unless specified otherwise, be a bonded carbon or nitrogen, wherein the -CH ₂ - 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

[00473] wherein “carbocyclyl” is a saturated, partially saturated or unsaturated, mono- or bicyclic carbon ring that contains 3-12 atoms; where the group -CH ₂ - can optionally be replaced by a group - C(O);

[00474] or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester or amide formed on an accessible carboxy or hydroxy group thereof.

[00475] In 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-(H-{(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-(H-{(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)-1-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 its salt.

[00476] In some embodiments, the compound of Formula V is

[00477] or

or

[00478] In some embodiments, an ASBTI suitable for the methods described herein is a compound of Formula VI:

[00479]

[00480] where:

[00481] R ^v and R ^w are independently selected from hydrogen or C _1-6 -alkyl;

[00482] 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;

[00483] 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;

[00484] 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;

[00485] n is 0-5;

[00486] one of R ⁴ and R ⁵ is a group of formula (VIA):

[00487]

[00488] 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-sulfamoyl; where R ³ and R ⁶ and the other of R ⁴ and R ⁵ may be optionally substituted on the carbon atom by one or more R ¹⁷ ;

[00489] X is -O-, -N(R ^a )-, -S(O) _b - or -CH(R ^a )-; where R ^a represents hydrogen or C _1-6 -alkyl, ab is equal to 0-2;

[00490] Ring A is aryl or heteroaryl; wherein ring A is optionally substituted on the carbon atom with one or more substituents selected from R ¹⁸ ;

[00491] R ⁷ is hydrogen, C _1-6 alkyl, carbocyclyl or heterocyclyl; where R ⁷ is optionally substituted on the carbon atom with one or more substituents selected from R ¹ 9; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ²⁰ ;

[00492] R ⁸ is hydrogen or C _1-6 alkyl;

[00493] R ⁹ is hydrogen or C _1-6 alkyl;

[00494] 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) ₂ -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) _r -R ²¹ -(C _1-10 -alkylene) _q - or heterocyclyl(C _1-10 -alkylene) _r -R ²² -(C _1-10 -alkylene ) _s -; where R ¹⁰ is optionally substituted on the carbon atom with one or more substituents selected from R ²³ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ²⁴ ; or R ¹⁰ represents a group of formula (VIB):

[00495]

[00496] where:

[00497] R ¹¹ represents hydrogen or C _1-6 -alkyl;

[00498] 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 ranges 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 be independently and optionally substituted on the carbon atom with one or more substituents selected from R ²⁵ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ²⁶ ;

[00499] 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) _r -R ²⁷ -(C _1-10 -alkylene) _q - or heterocyclyl(C _1-10 -alkylene) _r -R ²⁸ -(C _1-10 -alkylene ) _s -; where R ¹⁴ may be optionally substituted on the carbon atom with one or more substituents selected from R ²⁹ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ³⁰ ; or R ¹⁴ represents a group of formula (VIC):

[00500]

[00501] R ¹⁵ is hydrogen or C _1-6 alkyl;

[00502] R ¹⁶ represents hydrogen or C _1-6 -alkyl; where R ¹⁶ may be optionally substituted on the carbon atom by one or more groups selected from R ³¹ ;

[00503] n is 1-3; and the values of R ⁷ may be the same or different;

[00504] 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 and optionally substituted on a carbon atom by one or more R ³⁴ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be replaced by a group selected from R ³⁵ ;

[00505] 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 -; where R ³⁶ is selected from hydrogen or C _1-6 -alkyl, and x is equal to 0-2;

[00506] p, q, r and s are independently selected from 0-2;

[00507] 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, methyl ulfinyl a, mesyl, N-methyl sulfamoyl, N,N-dimethylsulfamoyl, N-methylsulfamoylamino and N,N-dimethylsulfamoylamino;

[00508] 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;

[00509] or a pharmaceutically acceptable salt, solvate or solvate of such a salt, or an in vivo hydrolyzable ester formed on its accessible carboxy or hydroxy, or an in vivo hydrolyzable amide formed on its accessible carboxy.

[00510] In some embodiments, a compound of Formula VI is characterized by the structure of Formula VID:

[00511]

[00512] where:

[00513] R ¹ and R ² are independently selected from C _1-6 alkyl; one of R ⁴ and R ⁵ represents a group of formula (VIE):

[00514]

[00515] 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 _1-4 -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-(C1-4-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 the carbon atom by one or more R ¹⁴ ;

[00516] 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 ), where R ^a and R ^b are independently selected from C _1-6 alkyl; or R ⁷ represents a group of formula (VIF):

[00517]

[00518] R ⁸ and R ⁹ independently represent hydrogen, C _1-4 alkyl or a saturated cyclic group, or R ⁸ and R ⁹ together form a C _2-6 alkylene; wherein R ⁸ and R ⁹ or R ⁸ and R ⁹ together may be independently and optionally substituted on the carbon atom with one or more substituents selected from R ¹⁵ ; and wherein, if said saturated cyclic group contains an -NH- moiety, this nitrogen may optionally be replaced by one or more R ²⁰ ;

[00519] R ¹⁰ is hydrogen or C _1-4 alkyl; where R ¹⁰ is optionally substituted on the carbon atom with one or more substituents selected from R ₂₄ ;

[00520] R ¹¹ is hydrogen, C _1-4 alkyl, carbocyclyl or heterocyclyl; where R ¹¹ is optionally substituted on the carbon atom with one or more substituents selected from R ¹⁶ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be substituted by one or more R ²¹ ;

[00521] R ¹² represents hydrogen or C _1-4 -alkyl, carbocyclyl or heterocyclyl; where R ¹² is optionally substituted on the carbon atom with one or more substituents selected from R ¹⁷ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be substituted by one or more R ²² ;

[00522] 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;

[00523] m is 1-3; moreover, the values of R ⁸ and R ⁹ may be the same or different;

[00524] n is 1-3; and the values of R ¹¹ may be the same or different;

[00525] p equals 1-3; and the values of R ¹² may be the same or different;

[00526] 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 and optionally substituted on a carbon atom by one or more R ¹⁸ ;

[00527] 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-(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, sulfo, sulfino, amidino, phosphono, -P(O)(OR ^e )(OR ^f ), -P(O)(OH)(OR ^e ), -P(O)(OH)(R ^e ) or - P(O)(OR ^e )( R ^f ), where R ^e and R ^f are independently selected from C _1-6 alkyl; wherein R ¹⁵ and R ¹⁷ may be independently and optionally substituted on a carbon atom by one or more R ¹⁹ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be substituted by one or more R ²³ ;

[00528] R ¹⁸ , R ¹⁹ and R ²⁵ are independently selected from halogen, hydroxy, cyano, carbamoyl, ureidoamine nitro, 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;

[00529] R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁶ are independently C _1-4 -alkyl, C _1-4 -alkanoyl, C _1-4 -alkylsulfonyl, sulfamoyl, N-(C _1-4 -alkyl)sulfamoyl, N,N-(C _1-4 -alkyl) ₂ -sulfamoyl, C _1-4 -alkoxycarbonyl, carbamoyl, N-(C _1-4 -alkyl)carbamoyl, N,N-(C _{1- 4} -alkyl) ₂ -carbamoyl, benzyl, phenethyl, benzoyl, phenylsulfonyl and phenyl;

[00530] 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 be independently and optionally substituted on a carbon atom by one or more R ²⁵ ; and wherein, if said heterocyclyl contains a -NH- group, this nitrogen may optionally be substituted by one or more R ²⁶ ;

[00531] 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;

[00532] wherein any heterocyclyl is a saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 3-12 atoms, at least one atom 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

[00533] wherein any carbocyclyl is a saturated, partially saturated or unsaturated, mono- or bicyclic carbon ring that contains 3-12 atoms, and the -CH ₂ - group can optionally be replaced by - C(O)-;

[00534] or a pharmaceutically acceptable salt thereof.

[00535] In 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 its salt.

[00536] 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 biodegradable polymer (eg, a polysaccharide).

[00537] In certain embodiments, the compounds described herein are not systemically absorbed. In addition, provided herein are compounds that inhibit the recycling of bile salts in the gastrointestinal tract of an individual. In some embodiments, compounds described herein may not be transported from the intestinal lumen and/or may not interact with ASBT. In some embodiments, the compounds described herein have no or minimal effect on 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, ASBTI is isolated from the distal ileum. ASBTI, compatible with the methods described herein, can be a direct inhibitor, an allosteric inhibitor, or a partial inhibitor of the apical sodium-dependent bile acid transporter.

[00538] In certain embodiments, compounds that inhibit ASBT or any regenerative bile acid transporters are those described in EP 1810689, US Pat. No. 6,458,851, 7,413,536, 7,514,421, US Patent Application Publication No. 2002/0147184, 2003/ 0119809, 2003/0149010, 2004/0014806, 2004/0092500, 2004/0180861, 2004/0180860, 2005/0031651, 2006/0069080, 2006/0199797, 2 006/0241121, 2007/0065428, 2007/0066644, 2007/0161578, 2007/0197628, 2007/0203183, 2007/0254952, 2008/0070888, 2008/0070892, 2008/0070889, 2008/0070984, 2008/0089858, 2008/00969 21, 2008/0161400, 2008/0167356, 2008/0194598, 2008/ 0255202, 2008/0261990, WO 2002/50027, WO2005/046797, WO2006/017257, WO2006/105913, WO2006/105912, WO2006/116499, WO2006/117076, 2006/121861, WO2006/122186, WO2006/124713, WO2007/050628 , WO2007/101531, WO2007/134862, WO2007/140934, WO2007/140894, WO2008/028590, WO2008/033431, WO2008/033464, WO2008/031501, 1500, 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 regenerative transport of bile acids are incorporated herein by reference.

[00539] In some embodiments, compounds that inhibit ASBT or any regenerative bile acid transporters are those 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, DE 19825804, WO00/38725, 8726, WO00/38727 ( including compounds with the structure of 2,3,4,5-tetrahydro-1-benzothiepine-1,1-dioxide), WO00/38728, WO01/66533, WO02/50051, EP0864582 (for example, (3R,5R)-3 -butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl(β-D-glucopyranosiduronic 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, 01/68096, WO02/ 08211, WO03/020710, WO03/022825, WO03/022830, WO03/0222861, JP10072371, US Patents No. 5910494; 5723458; 5817652; 5663165; 5998400; 6465451, 5994391; 6107494; 6387924; 6784201; 6875877; 6740663; 6852753; 5070103, 6114322, 6020330, 7179792, EP251315, EP417725, EP489-423, EP549967, EP573848, EP624593, EP624594, EP624595, EP869121, EP 10 70703, WO04/005247, drugs disclosed as having IBAT activity in Drags 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 regenerative transport of bile acids are incorporated herein by reference.

[00540] In some embodiments, compounds that inhibit ASBT or any regenerative 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 regenerative bile acid transporter include, but are not limited to, S-8921 (disclosed in EP597107, WO 93/08155), 264W94 (GSK) disclosed in WO 96/05188; 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]octanemethanesulfonate salt, SC-635 (Searle); ,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca); 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, ASBTI is:

[00541]

[00542]

[00543] In certain embodiments, the compounds described herein are characterized by one or more chiral centers. As such, all stereoisomers are provided herein. In various embodiments, the compounds described herein are present in optically active or racemic forms. It should be understood that the compounds of the present invention include racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof, that have the therapeutically beneficial properties described herein. Preparation of optically active forms is achieved by any suitable method, including, but not limited to, resolution of the racemic form by recrystallization methods, synthesis from optically active starting materials, chiral synthesis, or chromatographic resolution 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 number of methods, including enantioselective synthesis and/or resolution of a mixture of enantiomers and/or diastereomers. Separation of compounds and their isomers is achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, chromatography and the like.

[00544] In some embodiments, ASBTI is

[00545] (maralixibat, LUM-001, SHP625, lopixibate chloride) or an alternative pharmaceutically acceptable salt thereof.

[00546] In some embodiments, ASBTI is

[00547] (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)hydrosulfate) or its pharmaceutical form acceptable salt.

[00548] In some embodiments, ASBTI is

[00549] (LUM-002; SHP626; SAR548304; volixibate potassium) or an alternative pharmaceutically acceptable salt thereof.

[00550] In various embodiments, ASBTI is (odevixibate; AZD8294; WHO10706; AR-H064974; SCHEMBL946468; A4250; 1,1-dioxo-3,3-dibugyl-5-phenyl-7-methylthio-8-(N-{(N)-a-[N- ((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine) or a pharmaceutically acceptable salt thereof.

[00551] In some embodiments, ASBTI is (elobixibate; 2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfashgl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ,6,5 -benzothiazepine)-8-yl)oxy]acetyl]amino]-2-phenylacetyl]amino]acetic acid) or a pharmaceutically acceptable salt thereof.

[00552] In some embodiments, ASBTI is (GSK2330672; linerixibate; 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.

[00553] In some embodiments, the ASBTIs described herein are synthesized as described, for example, in WO 96/05188, US Pat. No. 5,994,391; 7238684; 6906058; 6020330 and 6114322.

[00554] In some embodiments, the ASBTI used in the methods or compositions of the present invention is maralixibate (SHP625), volixibate (SHP626), or odevixibate (A4250) or a pharmaceutically acceptable salt thereof.

[00555] In some embodiments, the ASBTI used in the methods or compositions of the present invention is maralixibat or a pharmaceutically acceptable salt thereof.

[00556] In some embodiments, the ASBTI used in the methods or compositions of the present invention is volixibate or a pharmaceutically acceptable salt thereof.

[00557] In some embodiments, the ASBTI used in the methods or compositions of the present invention is odevixibate or a pharmaceutically acceptable salt thereof.

[00558] In some embodiments, the ASBTI used in the methods or compositions of the present invention is elobixibate or a pharmaceutically acceptable salt thereof.

[00559] In some embodiments, the ASBTI used in the methods or compositions of the present invention is GSK2330672 or a pharmaceutically acceptable salt thereof.

[00560] In some embodiments, the ASBTI may comprise a mixture of different ASBTIs; for example, ASBTI may be a composition containing maralixibate, volixibate, odevixibate, GSK2330672, elobixibate, or various combinations thereof. Methods

[00561] Provided herein is a method for increasing height in a pediatric subject suffering from cholestatic liver disease. The method involves administering to the subject an effective amount of ASBTI. In various embodiments, the cholestatic liver disease is one of the childhood cholestatic liver diseases described above. In some embodiments, the cholestatic liver disease is PFIC, biliary atresia, or ALGS. In various embodiments, the cholestatic liver disease is PFIC 1, PFIC 2, or PFIC 3. In some embodiments, the patient has any childhood cholestatic condition resulting in below normal height or weight. In some embodiments, the patient has intrahepatic cholestasis of pregnancy (ICP).

[00562] In 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, post-Kasai biliary atresia , 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, neonatal sclerosing cholangitis, 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 , general parenteral nutrition-associated cholestasis, paraneoplastic cholestasis, Stauffer's syndrome, drug-associated cholestasis, infection-associated cholestasis, or cholelithiasis. In some embodiments, cholestatic liver disease is a childhood form of liver disease.

[00563] In certain embodiments, cholestatic liver disease is characterized by one or more symptoms selected from jaundice, pruritus, cirrhosis, hyperchoemia, neonatal respiratory distress syndrome, pulmonary pneumonia, elevated serum bile acid concentrations, elevated liver bile acid concentrations, increased serum bilirubin concentration, hepatocellular damage, 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, peculiar odor, dark urine, light-colored stools, steatorrhea, growth retardation and/or renal failure.

[00564] In certain embodiments, the methods of the present invention provide for the non-systemic administration of a therapeutically effective amount of ASBTI. In certain embodiments, the methods include contacting the gastrointestinal tract, including the distal ileum and/or colon and/or rectum, of a person in need thereof with ASBTI. In 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.

[00565] In various embodiments, the subject has a condition associated with, caused by, or caused in part by a deficiency of BSEP. In certain embodiments, the condition associated with, caused by, or partially caused by 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.

[00566] In various embodiments, the methods of the present invention provide for delivery to the ileum or colon of an individual a therapeutically effective amount of any ASBTI described herein.

[00567] In various embodiments, the methods of the present invention provide for reducing damage to hepatocellular or intestinal architecture or cells from cholestasis or cholestatic liver disease by administering a therapeutically effective amount of ASBTI. In some embodiments, the methods of the present invention comprise reducing bile acids/salts within enterocytes by administering a therapeutically effective amount of ASBTI to an individual in need thereof.

[00568] In some embodiments, the methods of the present invention comprise inhibiting the recycling of bile salts when any of the compounds described herein are administered to a subject. In some embodiments, the ASBTI described herein is absorbed systemically upon administration. In some embodiments, the ASBTI described herein is not systemically absorbed. In some embodiments, the ASBTI described herein is administered orally to a subject. In some embodiments, the ASBTI described herein is delivered and/or released into the distal ileum of a person.

[00569] 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 intra-enterocyte bile acids, reducing serum and/or liver bile acids, reducing the total serum bile acid load, and/or reducing damage to the ileal structure caused by cholestasis or cholestatic liver disease. Without being limited to any particular theory, reducing serum and/or hepatic bile acids improves hyperchoemia and/or cholestatic disease.

[00570] 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. introduction. Any compound or composition described herein can be administered in a manner or composition suitable for treating a newborn or infant. Any compound or composition described herein can be administered as an oral formulation (eg, solid or liquid) for treating a newborn or infant. Any compound or composition described herein can be administered before, with or after meals.

[00571] In 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, the amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the individual's medical condition, weight and response to drugs, and the judgment of the attending physician.

[00572] For prophylactic purposes, compounds or compositions containing 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 application, the exact amounts of compound administered depend on health status, weight, and the like. In addition, in some cases, when a compound or composition described herein is administered to an individual, effective amounts for that use will depend on the severity and course of the disease, disorder or condition, prior therapy, the individual's medical condition and response to drugs, as well as the conclusion attending physician.

[00573] In some embodiments of the methods of the present invention, in which 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, administration of the compound or composition described herein is optionally administered chronically, that is, over an extended period of time. 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.

[00574] In certain embodiments of the methods of the present invention, the 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 being treated, 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. In some embodiments, the doses administered include doses up to the maximum tolerated. In some embodiments, the doses administered include doses up to the maximum tolerated by the neonate or infant.

[00575] According to various embodiments of the methods of the present invention, the desired dose is typically in the form of a single dose or divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, in the form of two, three, four or more subdoses 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 a week. In some embodiments, the total unit dose of ASBTI is within the range described below.

[00576] According to various embodiments of the methods of the present invention, when the patient's condition does improve, ASBTI is optionally prescribed continuously at the physician's discretion; alternatively, the dose of the administered drug is temporarily reduced or temporarily suspended for a specified period of time (eg, a “drug holiday”). The length of the medication holiday may vary 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. Dose reductions during drug holidays include 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 unit dose of ASBTI is within the range described below.

[00577] After the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, 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 for any recurrence of symptoms.

[00578] In some cases, there are a large number of variables with respect to an individual treatment regimen, and significant deviations from these recommended values are considered within the scope described herein. The dosages described herein do not necessarily vary depending on a number of variables, such as, by way of non-limiting example, the activity of the compound being 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 attending physician.

[00579] The toxicity and therapeutic efficacy of such therapeutic regimens are not necessarily determined by pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of LD ₅₀ (dose lethal in 50% of the population) and ED ₅₀ (dose therapeutically effective in 50% of the population). % of the population). The dose ratio between toxic and therapeutic effects represents the therapeutic index and can be expressed as the ratio between LD ₅₀ and 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 dosage ranges for use in humans. In specific embodiments, the dosage of the compounds described herein is within a bloodstream concentration range that includes the ED ₅₀ with minimal toxicity. The dosage does not necessarily vary within this range depending on the dosage form used and the route of administration used.

[00580] In 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.

[00581] In some embodiments of the methods of the present invention, the composition used to prepare an oral dosage form or to be administered orally comprises an absorption inhibitor, an orally suitable carrier, an optional cholesterol absorption inhibitor, an optional enteroendocrine peptide, an optional peptidase inhibitor, an optional spreading agent, and optional moisturizer. In some embodiments, orally administered compositions produce an anorectal response. In specific embodiments, the anorectal response is an increase in the secretion of one or more enteroendocrines by cells of the colon and/or rectum (eg, L cells of the epithelial layer of the colon, ileum, rectum, or a combination thereof). In 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. In other embodiments, the anorectal response persists for a period of 24 hours to 48 hours, while in other embodiments, the anorectal response persists for a period greater than 48 hours.

Dosages

[00582] 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 subject is a newborn, a preterm neonate, an infant, a toddler, a preschooler, a school-age child, a pre-pubertal child, a post-pubertal child, a teenager, or a teenager under the age of eighteen. In some embodiments, the pediatric subject is a newborn, preterm neonate, infant, toddler, preschooler, or school-age child. In some embodiments, the pediatric subject is a newborn, preterm neonate, infant, toddler, or preschooler. In some embodiments, the pediatric subject is a newborn, preterm neonate, infant, or toddler. In some embodiments, the pediatric subject is a newborn, preterm newborn, or infant. In some embodiments, the pediatric subject is a newborn. In some embodiments, the pediatric subject is an infant. In some embodiments, the child subject is a toddler.

[00583] In various embodiments, ASBTI is maralixibate or volixibate, or a pharmaceutically acceptable salt thereof.

[00584] In various embodiments, the effectiveness and safety of administering ASBTI to a patient is monitored by measuring serum 7a-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, 7αC4 to sBA ratio (7αC4:sBA), total cholesterol concentration in serum, serum LDL-C cholesterol concentration, serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof. In various embodiments, the effectiveness of ASBTI administration is measured by monitoring observer-reported itching scores (ITCHRO(OBS)), HRQoL score (eg, PedsQL), CSS score, xanthoma score, height Z-score, weight Z-score, or various combinations thereof. In various embodiments, the method involves monitoring serum 7α-hydroxy-4-cholesten-3-one (7αC4), sBA concentration, 7αC4 to sBA ratio (7αC4:sBA), serum total cholesterol concentration, serum LDL-C cholesterol concentration , serum bilirubin concentration, serum ALT concentration, serum AST concentration, or combinations thereof. In various embodiments, the method includes monitoring an observer-reported itching score (ITCHRO(OBS)), an HRQoL score (eg, PedsQL), a CSS score, a xanthoma score, a height Z-score, a mass Z-score, or various combinations thereof.

[00585] In some embodiments, 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 µg/kg, 90 µg/kg, 100 µg/kg, 140 µg/kg, 150 µg/kg, 200 µg/kg, 240 µg/kg, 280 µg/kg, 300 µg/kg, 250 µg/kg, 280 µg/kg, 300 µg/kg, 400 µg/kg, 500 µg/kg, 560 µg/kg, 600 µg/kg, 700 µg/kg, 800 µg/kg, 900 µg/kg, 1000 µg/kg, 1100 µg/kg, 1200 µg/kg, 1300 µg/kg, 1400 µg/kg, 1500 µg/kg, 1600 µg/kg, 1700 µg/kg, 1800 µg/kg, 1900 µg/kg or 2000 µg/kg. In various embodiments, ASBTI is administered at a dose not exceeding about 1 μg/kg, 2 μg/kg, 3 μg/kg, 4 μg/kg, 5 μg/kg, 6 μg/kg, 7 μg/kg, 8 μg/kg. 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, 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, 2000 or 2100 mcg/kg. In various embodiments, 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, 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. 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 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 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 day.

[00586] In some embodiments, ASBTI is administered at a dose of from about 140 μg/kg/day to about 1400 μg/kg/day. In various embodiments, ASBTI is administered at a dose of about or at least about 0.5 μg/kg/day, 1 μg/kg/day, 2 μg/kg/day, 3 μg/kg/day, 4 μg/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, ASBTI is administered at a dose not exceeding about 1 μg/kg/day, 2 μg/kg/day, 3 μg/kg/day, 4 μg/kg/day, 5 μg/kg/day, 6 μg/day. 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 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, ASBTI is administered at a dose of from about 0.5 μg/kg/day to about 500 μg/kg/day, from about 0.5 μg/kg/day to about 250 μg/kg/day, from about 1 μg /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 approximately 2000 mcg/kg/day, approximately 280 mcg/kg/day to approximately 1400 mcg/kg/day, approximately 420 mcg/kg/day to approximately 1400 mcg/kg/day, about 250 mcg/kg/day to about 550 mcg/kg/day, about 560 mcg/kg/day to about 1400 mcg/kg/day, 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, about 300 mcg/kg/day to about 2000 mcg/kg/day, or about 400 mcg/kg/day to about 2000 mcg/kg/day.

[00587] In some embodiments, ASBTI is administered at a dose of from about 30 μg/kg to about 1400 μg/kg per dose. In some embodiments, the ASBTI is administered at a dose of from about 0.5 μg/kg to about 2000 μg/kg per dose, from about 0.5 μg/kg to about 1500 μg/kg per dose, from about 100 μg/kg to about 700 mcg/kg per dose, approximately 5 mcg/kg to approximately 100 mcg/kg per dose, approximately 10 mcg/kg to approximately 500 mcg/kg per dose, approximately 50 mcg/kg to approximately 1400 mcg/kg per dose 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 approximately 700 mcg/kg per dose, 80 mcg/kg to approximately 1000 mcg/kg per dose, 80 mcg/kg to approximately 800 mcg/kg per dose, 100 mcg/kg to approximately 800 mcg /kg per dose, 100 mcg/kg to approximately 600 mcg/kg per dose, 150 mcg/kg to approximately 700 mcg/kg per dose, 150 mcg/kg to approximately 500 mcg/kg per dose, 200 mcg /from 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.

[00588] In some embodiments, ASBTI is administered at a dose of from about 0.5 mg/day to about 550 mg/day. In various embodiments, 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, about 5 mg/day to about 150 mg/day, about 5 mg/day to about 100 mg/day, 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 about 30 mg/day.

[00589] In some embodiments, ASBTI is administered twice daily (BID) in an amount of from about 200 μg/kg to about 400 μg/kg per dose. In some embodiments, ASBTI is administered in an amount of from about 280 μg/kg/day to about 1400 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 400 μg/kg/day to about 800 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 20 mg/day to about 50 mg/day. In some embodiments, ASBTI is administered in an amount of from about 5 mg/day to about 15 mg/day. In some embodiments, ASBTI is administered in an amount of from about 560 μg/kg/day to about 1400 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 700 μg/kg/day to about 1400 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 400 μg/kg/day to about 800 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 700 μg/kg/day to about 900 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 560 μg/kg/day to about 1400 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from 700 μg/kg/day to about 1400 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 200 μg/kg/day to about 600 μg/kg/day. In some embodiments, ASBTI is administered in an amount of from about 400 μg/kg/day to about 600 μg/kg/day.

[00590] In various embodiments, the dose of ASBTI is a first dose amount. In various embodiments, the dose of ASBTI is a second dose amount. In some embodiments, the second dose amount is greater than the first dose amount. In some embodiments, the second dose amount 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 more than the first dose value. In 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 more than the first dose value.

[00591] In various embodiments, ASBTI is administered once daily (QD) at one of the above dosages or within one of the above dosage ranges. In various embodiments, ASBTI is administered twice daily (BID) at one of the above dosages or in one of the above dosage ranges. In various embodiments, the dose of ASBTI is administered daily, every other day, twice a week, or once a week.

[00592] In various embodiments, 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, ASBTI is administered for no more than 1, 2, 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, ASBTI is administered regularly for about or at least about 0.5, 1, 1.5, 2, 3, 5, 6, 7, 8, 9, or 10 years. in various embodiments, ASBTI is administered regularly over a period not exceeding about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 years.

Reduction of symptoms or disease-related laboratory values of cholestatic liver disease

[00593] According to various embodiments of the above methods of the present invention, administration of ASBTI results in a reduction in symptom or change in disease-related laboratory parameters of cholestatic liver disease (i.e., improvement in the patient's condition) that lasts 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, 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 of a symptom or change in laboratory parameters related to the disease includes 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 ALT, an increase in a quality of life score, an increase in fatigue-related quality of life score, a decrease in serum total cholesterol concentration, a decrease in serum LDL-C cholesterol concentration, an increase in height, a decrease in the number of xanthomas, or various combinations thereof. In various embodiments, the reduction of a symptom or change in laboratory parameters related to the disease is determined relative to a baseline. That is, a decrease in a symptom or change in a disease-related laboratory value is determined relative to the measurement of the symptom or change in a disease-related laboratory value prior to 1) a change in the amount of ASBTI dose administered to the patient, 2) a change in the dosing regimen followed by the patient, 3) initiation of administration ASBTI or 4) any other miscellaneous changes made to reduce a symptom or change laboratory values related to a disease in a patient. In various embodiments, the reduction in a symptom or change in laboratory parameters related to the disease represents a statistically significant reduction.

[00594] In various embodiments, a decrease in a symptom or change in a disease-related laboratory value of cholestatic liver disease is measured as a progressive decrease 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.

[00595] In some embodiments, the patient is a pediatric patient, and the decrease in symptoms or change in laboratory parameters related to the disease includes an increase in height. In some embodiments, the increase in height is measured relative to a baseline. In various embodiments, an increase in height is measured as an increase in a height Z-score or a weight Z-score. In various embodiments, the increase in height Z-score or weight Z-score is statistically significant. In various embodiments, the height Z-score, the weight Z-score, or both are increased 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, .56, .57, .58, .59, .6, .7, .8, or .9 relative to baseline. In some embodiments, the height Z-score, weight Z-score, or both increases progressively during administration of ASBTI 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.

[00596] In various embodiments, administration of ASBTI results in an increase in serum 7aC4 concentration. In various embodiments, the serum 7aC4 concentration 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 the original level. In various embodiments, serum 7aC4 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.

[00597] In various embodiments, administration of ASBTI results in an increase in the 7aC4:sBA ratio of about or at least about 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 10000 times the original level.

[00598] In various embodiments, administration of ASBTI results in increased excretion of fBA. In some embodiments, administration of 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 the original level. In various embodiments, ASBTI is administered at a dose sufficient to cause an increase in bile acid secretion relative to baseline by 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 original level. In some embodiments, fBA excretion 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 initial level. In various embodiments, administration of ASBTI results in a dose-dependent increase in fBA excretion such that administration of a higher dose of ASBTI results in a corresponding higher level of fBA excretion.

[00599] In various embodiments, administration of ASBTI results in a reduction in sBA concentration of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% relative to baseline.

[00600] In some embodiments, administration of ASBTI results in a decrease in the severity of itching. In various embodiments, the severity of itching is measured using an ITCHRO(OBS) score, an ITCHRO score, a CSS score, or a combination thereof. In various embodiments, administration of 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 the initial level. In various embodiments, administration of 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 ASBTI causes the ITCHRO(OBS) score, the ITCHRO score, or both to decrease to zero. In various embodiments, administration of ASBTI causes the ITCHRO(OBS) score or ITCHRO score to decrease to 1.0 or lower. In various embodiments, administration of ASBTI results in a decrease in CSS score of 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 baseline. In various embodiments, the introduction of ASBTI causes the CSS score to decrease to zero. In various embodiments, administration of ASBTI results in a reduction in CSS score, ITCHRO(OBS) score, ITCHRO score, or a combination thereof of 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. In various embodiments, a reduction from baseline in the CSS score, ITCHRO(OBS) score, ITCHRO score, or a combination thereof is observed by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75% , 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% days.

[00601] In various embodiments, administration of ASBTI results in a decrease in serum LDL-C concentration compared to baseline. In some embodiments, serum LDL-C concentration is reduced 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 baseline.

[00602] In some embodiments, administration of ASBTI results in a decrease in serum total cholesterol concentration compared to baseline. In some embodiments, administration of ASBTI results in a decrease in serum LDL-C levels compared to baseline. In some embodiments, serum total cholesterol concentration, serum LDL-C content, or both are reduced 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 baseline. In various embodiments, administration of ASBTI results in a decrease in serum total cholesterol concentration, serum LDL-C concentration, 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 from baseline.

[00603] 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 represent a measure of health-related quality of life (HRQoL). In some embodiments, the HRQoL measure is a PedsQL score. In various embodiments, administration of ASBTI results in an increase in PedsQL score or fatigue-related PedsQL score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 45%, or 50% relative to initial level.

[00604] In various embodiments, administration of ASBTI results in a decrease in the xanthoma score compared to baseline. In some embodiments, the xanthoma rate 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% relative to baseline.

[00605] In various embodiments, administration of ASBTI results in a reduction in symptom or change in laboratory parameters related to the disease by approximately 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.

[00606] In various embodiments, the serum bilirubin concentration is at baseline before administration or at normal levels after approximately 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.

[00607] In various embodiments, the serum ALT concentration is at baseline before administration or at normal levels after approximately 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 ASBTI results in a reduction in ALT from baseline of about or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% , 11%, 12%, 13%, 14% or 15%.

[00608] In various embodiments, the serum ALT concentration, serum AST concentration, serum bilirubin concentration, or various combinations thereof are within the normal range or pre-administration baseline at approximately 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 week, 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 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 approximately 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. Introduction of ASBTI to increase height.

[00609] In various embodiments, administration of ASBTI results in an increase in height or weight in approximately 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 or 1 year or approximately this period.

[00610] In some embodiments, the height increase 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.

[00611] In 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.

[00612] In various embodiments, the method comprises administering a first dose amount of ASBTI to a patient. In some embodiments, the method further comprises administering a second dose amount of ASBTI greater than the first dose amount following the first administration of the first dose amount of ASBTI over a period of time. In various embodiments, the time period 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.

[00613] In some embodiments, the weight or height Z-score increases in a dose-dependent manner in response to administration of ASBTI such that the second dose results in a greater increase in the weight or height Z-score. In some embodiments, if the first dose does not result 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 from baseline, then the patient is given the second dose in this manner 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 baseline.

[00614] In various embodiments, administration of a first dose or a second dose of BID at a constant total daily dose results in a greater increase in height than administration of a total daily dose of the same QD level.

[00615] In various embodiments, the second dose is the total daily dose administered by the BID. In various embodiments, the second dose results in an increase in height above the baseline measured at the time of the first dose. In various embodiments, the second dose results in a greater increase in height from baseline measured before administration of the ASBTI than the increase in height from baseline caused by the administration of the first dose. In various embodiments, administration of the second dose results in an increase in Z-score of 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 initial height Z-score measured at the time of the patient's first dose. In various embodiments, administration of the second dose results in an increase in the Z-score compared to the baseline measured before ASBTI administration 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 Z-score from baseline measured before ASBTI administration caused by ASBTI administration at the first dose.

Genotype PFIC 2

[00616] 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% of the BSEP function relative to a healthy individual without cholestatic liver disease. In various embodiments, the patient has a maximum of approximately 99%, 95%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 25%, 20%, 5%, 2.5% BSEP functions relative to a healthy person without cholestatic liver disease. BSEP deficiency can lead to impaired or decreased bile flow or cholestasis.

[00617] In various embodiments, 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 in the ABCB11 gene result in no residual function of the encoded BSEP (a “severe” mutation). In various embodiments, the ABCB11 gene contains a mutation and does not contain any truncating mutations. The ABCB11 gene mutation may be a missense or nonsense mutation, an insertion or a deletion. In embodiments, the ABCB11 gene contains the E297G or D482G mutation, or both, alternatively referred to as “mild” mutations or “mild PFIC 2.” In some embodiments, the ABCB11 gene contains a missense mutation and does not contain the E297G or D482G missense mutation, alternatively referred to as “medium” mutations or “medium PFIC 2.” The ABCB11 gene may contain 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 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.

[00618] In various embodiments, the patient has a complete loss of BSEP activity. In various embodiments, a patient with complete loss of BSEP activity is homozygous for the ABCB11 genes having mutations that result in complete loss of the encoded BSEP activity (eg, 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 the ABCB11 gene having mutations resulting in complete loss of the encoded BSEP activity (e.g., patients having the ABCB11 gene with a truncating mutation and a wild-type ABCB11 gene, or patients having the ABCB11 gene with a truncating mutation and the ABCB11 gene, which has mutations encoding BSEP, which has residual activity, but activity that is reduced compared to wild-type BSEP). In certain embodiments, the person with residual BSEP activity is homozygous for ABCB11 genes having mutations resulting in residual BSEP activity and reduced BSEP activity compared to the wild type (eg, patients having ABCB11 genes with the same or different missense mutations). In some embodiments, a patient having residual BSEP activity is heterozygous for ABCB11 genes having mutations resulting in residual BSEP activity and reduced BSEP activity compared to the wild type (e.g., patients having a wild-type ABCB11 gene and a missense ABCB11 gene). mutation).

[00619] In various embodiments, the method involves determining the genotype of a patient. Genotyping may involve any of various methods known in the art for determining the gene sequence for a patient, including, but not limited to, genomic DNA restriction fragment length polymorphism identification, random amplified genomic DNA polymorphism detection, length polymorphism detection amplified fragment, polymerase chain reaction, DNA sequencing, allele-specific oligonucleotide probes, hybridization with DNA microarrays or beads, and various combinations thereof. In various embodiments, determining the genotype includes determining the sequence of the gene, ABCB11.

[00620] In some embodiments, genotyping involves identifying and characterizing a mutation in the ABCB11 gene. Determination of the genotype may involve determination of the sequence for part or all of the ABCB11 gene. Determination of the genotype may further involve determining the sequence of the genomic region surrounding the ABCB11 gene, or determining the sequence for one or more introns and/or exons of the ABCB11 gene. Genotyping may involve characterizing the ABCB11 gene by identifying one, more, or all mutations of the alleles encoding the ABCB11 gene in a patient. In various embodiments, genotyping involves determining whether the ABCB11 gene has a truncating mutation, insertion, deletion, missense mutation, E197G mutation, D482G mutation, or various combinations thereof. Dose modulation

[00621] In various embodiments, the method involves changing the dosage of ASBTI administered to a patient. Modulation involves determining the patient's 7αC4:sBA ratio at baseline (eg, prior to administration of ASBTI or before modulating (eg, increasing) the ASBTI dosage) and further determining the 7αC4:sBA ratio after administering the first dose of ASBTI or modulating (eg, increasing) the amount ASBTI dosage prior to the 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 the baseline, ASBTI dose is increased until the ratio increases at least approximately 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 10000 times the original level. In various embodiments, the dose of ASBTI is increased or decreased to achieve and maintain a specific 7αC4:sBA ratio.

[00622] In various embodiments, the modulation involves increasing the dose of ASBTI from a first dose value to a second dose value greater than the first dose value 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, 1000, 2000 , 3000, 4000, 5000 or 10000 times the original level, 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 10000 times or more, compared with the original level. 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 10000 times the original level.

[00623] In some embodiments, the modulation involves administering a first dose of 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 given a second dose of ASBTI 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 10000 times the original level.

[00624] In 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 necessary each time the ratio is measured. Pharmaceutical compositions

[00625] In some embodiments, ASBTI is administered in the form of a pharmaceutical composition containing ASBTI (composition or 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, transverse colon, and/or ascending colon. In even more specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and/or colon by rectal administration. In other specific embodiments, the composition is formulated for non-systemic or local delivery to the rectum and/or colon, administered orally.

[00626] 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 contains an ASBT inhibitor (eg, any ASBTI described herein).

[00627] In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, including, for example, excipients and excipients that facilitate processing of the active compounds into preparations suitable for pharmaceutical use. In certain embodiments, the correct formulation depends on the route of administration chosen. A summary of the pharmaceutical compositions described herein can be found, for example, in 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.

[00628] 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, thickeners and/or excipients. In some cases, the pharmaceutical composition facilitates administration of the compound to an individual or into 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 certain 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.

[00629] In 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.

[00630] In certain embodiments, the pharmaceutical compositions described herein include one or more compounds described herein as an active ingredient in free acid or free base form or in pharmaceutically acceptable salt form. In some embodiments, the compounds described herein are used in N-oxide form or in crystalline or amorphous form (ie, a polymorph). In some situations, the compound described herein exists as tautomers. All tautomers are included within the scope of the compounds presented 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. olvated forms of the compounds presented herein are also considered to be described herein.

[00631] A “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 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, 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.

[00632] Additionally, in some embodiments, the pharmaceutical compositions described herein are formulated in a dosage form. Thus, in some embodiments, provided herein is a dosage form containing 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, rapid 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.

[00633] In 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.

[00634] In certain embodiments, the composition comprises an enteroendocrine peptide secretagogue and an absorption inhibitor. In specific embodiments, an absorption inhibitor is an inhibitor that inhibits the absorption of (or at least one of) the 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 (eg, an oral carrier or a rectal carrier, depending on the intended route of 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.

[00635] In other embodiments, the compositions described herein are administered orally for non-systemic delivery of ASBTI to the rectum and/or colon, including the sigmoid colon, transverse colon, and/or ascending colon. In specific embodiments, the 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

[00636] In certain embodiments, a composition described herein as formulated for non-systemic delivery of ASBTI further comprises an absorption inhibitor. As used herein, an absorption inhibitor includes an agent or group of agents that inhibits the absorption of bile acid/salt.

[00637] Suitable bile acid absorption inhibitors (also described herein as absorption inhibitors) may include, but are not limited to, anion exchange matrices, polyamines, quaternary amine polymers, quaternary ammonium salts, polyallylamine polymers and copolymers, colesevelam, Colesevelam hydrochloride, cholestagel (N,N,N-trimethyl-6-(2-propenylamino)-1-hexanaminium 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 protein substances, as well as bile acid-binding antibodies and albumins. Suitable cyclodextrins include those that bind bile acids/salts, such as, by way of non-limiting example, β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Suitable proteins include those that bind bile acids/salts, such as, by way of non-limiting example, bovine serum albumin, egg albumin, casein, α-acid glycoprotein, gelatin, soy proteins, peanut proteins, almond proteins and wheat vegetable proteins. .

[00638] In certain embodiments, the absorption inhibitor is cholestyramine. In specific embodiments, cholestyramine is combined with a bile acid. Cholestyramine, an ion exchange resin, is a styrene polymer containing quaternary ammonium groups cross-linked with divinylbenzene. In other embodiments, the absorption inhibitor is colestipol. In specific embodiments, colestipol is combined with a bile acid. Colestipol, an ion exchange resin, is a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane.

[00639] In certain embodiments of the compositions and methods described herein, ASBTI is associated with an absorption inhibitor, while in other embodiments, ASBTI and the absorption inhibitor are separate molecular entities.

Cholesterol absorption inhibitors

[00640] In some embodiments, a composition described herein optionally includes at least one cholesterol absorption inhibitor. Suitable cholesterol absorption inhibitors include, by way of non-limiting example, ezetimibe (SCH 58235), ezetimibe analogs, AST inhibitors, stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholine analogs, β-lactam cholesterol absorption inhibitors, sulfate polysaccharides, non-insomycin, plant saponins, plant sterols, phyto stanol FM-VP4, sitostanol, β-sitosterol, acyl-CoA:cholesterol-O-acyltransferase (ACAT) inhibitors, avasimib, implitapide, steroidal glycosides, etc. Suitable enzetimibe analogs include, but are not limited to, SCH 48461, SCH 58053, and the like. Suitable ACT inhibitors include, by way of non-limiting example, trimethoxy fatty acid anilides such as C1-976, 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

[00641] 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, candoxatrylate and ecadotril.

Flow enhancers/wetting agents

[00642] In certain embodiments, the composition described herein optionally contains a spreading agent. In some embodiments, a spreading agent is used to improve distribution of the composition in the colon and/or rectum. Suitable spreading agents include, by way of non-limiting example, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, colloidal silica, propylene glycol, cyclodextrins, microcrystalline cellulose, polyvinylpyrrolidone, polyoxyethylated glycerides, polycarbophil, di-n-octyl ethers, Cetiol™OE, polyalkylene ethers glycol fatty alcohols, Aethoxal™B), 2-ethylhexyl palmitate, Cegesoft™C24) and isopropyl fatty acid esters.

[00643] In some embodiments, the compositions described herein optionally contain a wetting agent. In some embodiments, a 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 not limited to, polysorbate (e.g., 20 or 80), stearyl getanoate, caprylic/capric fatty acid esters, and saturated fatty alcohols with a chain length of C ₁₂ -C ₁₈ , isostearyl diglycerol-isostearic acids, sodium dodecyl sulfate, isopropyl myristate, isopropyl palmitate and isopropyl myristate/isopropyl stearate/isopropyl palmitate mixtures.

Vitamins

[00644] In some embodiments, the methods provided herein further comprise the administration of one or more vitamins.

[00645] In 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.

[00646] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherols, phylloquinone. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

Bile acid sequestrants/binders

[00647] 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 containing pectin, galactomannan and/or azohydrogels and/or glycoside conjugates (eg, D-galactoside, β-D-xylopyranoside conjugates, 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 and the like.

[00648] 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 approximately 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 in approximately 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.

[00649] In some embodiments, the labile bile acid sequestrant has low affinity for bile acid. In some embodiments, the labile bile acid sequestrant has high affinity for primary bile acid and low affinity for secondary bile acid.

[00650] 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 bile acid at a pH value of 6 or lower and a low affinity for bile acid at a pH value above 6. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 6.5 or lower and low affinity for bile acid at a pH value above 6.5. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7 or lower and a low affinity for bile acid at a pH value above 7. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7.1 or lower and low affinity for bile acid at a pH value above 7.1. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7.2 or lower and a low affinity for bile acid at a pH value above 7.2. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7.3 or lower and a low affinity for bile acid at a pH value above 7.3. In some embodiments, the pH-dependent bile acid sequestrant has high affinity for bile acid at a pH value of 7.4 or lower and low affinity for bile acid at a pH value above 7.4. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7.5 or lower and a low affinity for bile acid at a pH value greater than 7.5. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7.6 or lower and a low affinity for bile acid at a pH value greater than 7.6. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7.7 or lower and a low affinity for bile acid at a pH value greater than 7.7. In some embodiments, the pH-dependent bile acid sequestrant has a high affinity for bile acid at a pH value of 7.8 or lower and a low affinity for bile acid at a pH value above 7.8. In some embodiments, the pH-dependent bile acid sequestrant is degraded at a pH value greater than 6. In some embodiments, the pH-dependent bile acid sequestrant is degraded at a pH value greater than 6.5. In some embodiments, the pH-dependent bile acid sequestrant is degraded at a pH greater than 7. In some embodiments, the pH-dependent bile acid sequestrant is degraded at a pH greater than 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 above 7.5. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.6. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.7. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.8. In some embodiments, the pH-dependent bile acid sequestrant degrades at a pH above 7.9.

[00651] In certain embodiments, the labile bile acid sequestrant is 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 containing 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, which are described, for example, in US Pat. No. 3,383,281; 3308020; 3769399; 3846541; 3974272; 4172120; 4252790; 4340585; 4814354; 4874744; 4895723; 5695749 and 6066336, all of which are incorporated herein by reference in their entirety for all purposes. In some embodiments, the bile acid binder is cholestipol or cholezevelam.

Routes of administration, dosage forms and dosage regimens

[00652] 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 bile acid levels in the serum or liver. 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 local 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 in the form of enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. In some embodiments for oral administration, the compositions described herein are formulated for oral administration and enteric delivery to the colon.

[00653] In certain embodiments, the compositions or methods described herein are not systemic. In some embodiments, the compositions described herein deliver ASBTI to the distal ileum, colon, and/or rectum rather than systemically (eg, a significant portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, oral compositions described herein deliver ASBTI to the distal ileum, colon, and/or rectum rather than systemically (eg, a substantial portion of the enteroendocrine peptide secretagogue is not systemically absorbed). In some embodiments, the rectal compositions described herein deliver ASBTI to the distal ileum, colon, and/or rectum rather than systemically (eg, 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 ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 80% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 70% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 60% by weight of ASBTI. In certain embodiments, the non-systemic compositions described herein systemically deliver less than 50% by weight of 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, and the like.

[00654] In certain embodiments, the compositions and/or formulations described herein are administered at least once daily. In certain embodiments, ASBTI-containing formulations are administered at least twice daily, while in other embodiments, ASBTI-containing formulations are administered at least three times daily. In certain embodiments, ASBTI-containing formulations are administered up to five times daily. It should be understood that, in certain embodiments, the dosage regimen for the ASBTI-containing composition described herein is determined by taking into account various factors, such as the age, gender, and diet of the patient.

[00655] The concentration of ASBTI administered in the compositions described herein ranges from about 1 mM to about 1 M. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 1 mM to about 750 mM. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 1 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 5 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 10 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 25 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 50 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 100 mM to about 500 mM. In certain embodiments, the concentration of ASBTI administered in the compositions described herein ranges from about 200 mM to about 500 mM.

[00656] In certain embodiments, by targeting the distal gastrointestinal tract (e.g., distal ileum, colon, and/or rectum), the compositions and methods described herein provide effectiveness (e.g., in reducing microbial growth and /or relief of symptoms of cholestasis or cholestatic liver disease) with a reduced dose of an enteroendocrine peptide secretagogue (eg, compared with an oral dose that does not target the distal gastrointestinal tract). Formulations for rectal administration

[00657] Pharmaceutical compositions described herein for non-systemic delivery of a compound described herein to the rectum and/or colon are formulated for rectal administration in the form of 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, pharmaceutical compositions and compositions are or contain the compositions described herein. In some embodiments, rectal formulations include rectal enemas, foams, gels, or suppositories.

[00658] In certain embodiments, liquid excipients or co-solvents of carriers in the compositions and/or formulations described herein include, by way of non-limiting example, purified water, propylene glycol, PEG200, PEG300, PEG400, PEG600, polyethylene glycol, ethanol, 1-propanol , 2-propanol, 1-propen-3-ol (allylic alcohol), propylene glycol, glycerin, 2-methyl-2-propanol, formamide, methylformamide, dimethylformamide, ethylformamide, diethylformamide, acetamide, methylacetamide, dimethylacetamide, ethyl acetamide, 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 , pyruvicaldehyde dimethyl acetal, dimethyl isosorbide and combinations thereof.

[00659] In 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.

[00660] In certain embodiments, surfactants/emulsifiers used in the compositions and/or formulations described herein include, by way of non-limiting example, cetostearyl alcohol-sorbitan mixtures, 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 meroxapols, 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, pharmaceutically acceptable salts thereof, and combinations thereof.

[00661] 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 (cetet-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 (PEG-50 stearate), 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 23 1) , 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.

[00662] In 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 their combinations.

[00663] In 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 fat and combinations thereof.

[00664] In certain embodiments, thickeners 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, by way of non-limiting example, gum arabic, agar, alginates, carrageenan, guar, arabic, tragacanth, pectins, dextran, gellan and xanthan gums. Semi-synthetic polymers include, by way of non-limiting example, cellulose esters, modified starches, modified celluloses, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Synthetic polymers include, by way of non-limiting example, polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyacrylates, carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones), polyvinyl acetate, polyethylene glycols and poloxamer. Other thickeners include, by way of non-limiting example, 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.).

[00665] In some embodiments, chelating agents used in the compositions and/or formulations described herein include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or salts, phosphates, and combinations thereof.

[00666] In some embodiments, the concentration of the chelating agent or agents used in the rectal formulations described herein is a suitable concentration, for example, about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5% (w/v).

[00667] In some embodiments, preservatives used in the compositions and/or formulations described herein include, by way of non-limiting example, 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.

[00668] In 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, sulfite sodium, sodium bisulfite, sodium formaldehyde sulfoxylate, potassium metabisulfite, sodium metabisulfite, oxygen, quinones, tert-butylhydroquinone, erythorbic acid, olive (olea eurpaea) oil, penetatate pentasodium, pentetic acid, tocopheryl, tocopheryl acetate and combinations thereof.

[00669] In some embodiments, the concentration of the antioxidant or antioxidants used in the rectal formulations described herein is sufficient to achieve the desired result, for example, about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5% (w/v).

[00670] Lubricants used in the compositions and/or formulations described herein include, by way of non-limiting example, natural or synthetic fat or oil (eg, 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.

[00671] In 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, by way of non-limiting example, hydroxypropylcellulose, polyethylene oxide homopolymers, polyvinylether-maleic acid copolymers, methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polycarbophil, polyvinylpyrrolidone, bopol, polyurethanes, polyethylene oxide copolymers and polypropylene oxide, sodium carboxymethylcellulose, 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, caraya, tragacanth, algin, chitosan, stacharides, pectins and their combinations.

[00672] In some embodiments, pH adjusting buffers/agents used in the compositions and/or formulations described herein include, but are not limited to, phosphoric acid, monobasic sodium or potassium phosphate, triethanolamine (TRIS), BICINE, HEPES , Trizma, glycine, histidine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, carbonate, bicarbonate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, acetic acid, acetate, citric acid, anhydrous sodium citrate, sodium citrate dihydrate and their combinations. 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.

[00673] In 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 desirable pH, e.g., about 0.1%, 0.2%, 0.3% , 0.4%, 0.5%, 0.6%, 0.8%, 0.9% or 1.0% (w/w).

[00674] 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

[00675] In certain aspects, a composition or formulation containing one or more compounds described herein is administered orally for local delivery of 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 contain the compositions described herein contained in or enclosed in microspheres. In some embodiments, the microspheres include, by way of non-limiting example, HPMC chitosan microporous capsules and cellulose acetate butyrate (CAB) microspheres. In certain embodiments, oral dosage forms are prepared using conventional methods known to those skilled in the pharmaceutical art. For example, in certain embodiments, tablets are manufactured using standard tablet processing procedures and equipment. An exemplary tablet forming method is direct compression of a powder, 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, the tablets are molded rather than compressed starting from a wet or pliable material.

[00676] In certain embodiments, tablets formulated for oral administration contain various excipients, including, but not limited to, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents , flavorings, etc. In some embodiments, binders are used to impart cohesive properties to the tablet to ensure that the tablet remains intact after compression. Suitable binders include, by way of non-limiting example, 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, for example, sodium alginate gum, polyvinylpyrrolidone, cellulose polymers (including hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, etc.), vigum and combinations thereof. In certain embodiments, diluents are used to increase the volume of the tablet so that a tablet of practical size is obtained. Suitable diluents include, by way of non-limiting example, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry sugar, powdered sugar, and combinations thereof. In certain embodiments, lubricants are used to facilitate tablet manufacturing; examples of suitable lubricants include, by way of non-limiting example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn and cocoa butter, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. In some embodiments, disintegrants are used to facilitate tablet disintegration and include, but are not limited to, starches, clays, celluloses, algins, gums, cross-linked polymers, and combinations thereof. Fillers include, by way of non-limiting example, materials such as silica, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. In certain embodiments, stabilizers are used to inhibit or slow down drug degradation reactions, which include, for example, oxidative reactions. In certain embodiments, the surfactants are anionic, cationic, amphoteric, or nonionic surfactants.

[00677] In some embodiments, ASBTI or other compounds described herein are administered orally in combination with a carrier suitable for delivery to the distal gastrointestinal tract (eg, distal ileum, colon, and/or rectum).

[00678] 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 contains a polymer that is pH sensitive (eg, 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, e.g., Carbopol® polymers) that contain acidic groups (e.g. -COOH, -SO ₃ H) and swell to an alkaline intestinal pH (eg, pH of about 7 to about 8). In some embodiments, a composition suitable for controlled release in the distal ileum comprises a microparticulate active agent (eg, a micronized active agent). In some embodiments, the non-enzymatically degradable lactic-glycolic acid (PLGA) copolymer core is suitable for delivering an enteroendocrine peptide secretagogue to the distal ileum. In some embodiments, the dosage form containing 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, or the like .) 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 (eg, D-galactoside, β-D-xylopyranoside conjugates, 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 and the like.

[00679] The pharmaceutical composition described herein optionally contains an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives, such as a compatible carrier, binder, excipient, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, active agent, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration enhancer, wetting agent, defoamer, 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 a composition of a compound of Formula I. In one embodiment, the compound described herein is in particulate form, and some or all of the particles of the compound are characterized by a coating. In some embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of a compound described herein are not microencapsulated or coated.

[00680] In additional embodiments, a tablet or capsule containing ASBTI or other compounds described herein is characterized by 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, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, and the like. Dosage forms and compositions for pediatric patients

[00681] 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 contains an ASBT inhibitor (eg, any ASBTI described herein).

[00682] In some embodiments, suitable dosage forms for a dosage form or composition for pediatric patients include, by way of non-limiting example, aqueous or non-aqueous oral dispersions, liquids, gels, syrups, elixirs, suspensions, solutions, controlled release formulations , rapid melting formulations, effervescent formulations, lyophilized formulations, chewable tablets, gummy candies, oral disintegrating tablets, powders for dissolution as suspension or solution, powdered oral powders or granules, dragees, sustained release formulations, extended release formulations , pulsatile release formulations, multiparticulate formulations and mixed immediate and controlled release formulations. In some embodiments, provided herein is a pharmaceutical composition wherein the dosage form for pediatric patients is selected from a solution, syrup, suspension, elixir, powder to be dissolved as a suspension or solution, dispersible/effervescent tablet, chewable tablet, chewable candy, lozenge lollipops, freezer lozenges, lozenges, oral thin strips, oral disintegrating tablet, oral strips, sachets and oral powder or granules.

[00683] In another aspect, provided herein is a pharmaceutical composition wherein at least one excipient is a flavoring or sweetening agent. In some embodiments, coverage is provided herein. In some embodiments, provided herein is a taste masking technology selected from coating drug particles with a taste-neutral polymer by spray drying, wet granulation, fluidized bed, and microencapsulation; molten paraffin coating from a mixture of molten waxes and other pharmaceutical adjuvants; entrapment of drug particles by complexation, flocculation or coagulation of the aqueous polymer dispersion; adsorption of drug particles on resin 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. In some embodiments, provided herein is a delayed or sustained release formulation comprising drug particles or granules in a rate-controlling polymer or matrix.

[00684] Suitable sweeteners include sucrose, glucose, fructose or intense sweeteners, i.e. agents with a high sweetening power compared to sucrose (for example, 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, palatinite, stevioside, rebaudioside, Magnasvit®. The total concentration of sweeteners can vary from essentially zero to about 300 mg/ml based on the liquid composition after dissolution.

[00685] To enhance the palatability of the liquid composition when dissolved in an aqueous medium, one or more flavoring agents 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 sweetener(s) and flavor(s).

[00686] A flavoring agent as used herein is a substance capable of enhancing the taste or aroma of a composition. Suitable natural or synthetic flavors 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 formulations 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, chewing gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cold cherry, cold citrus, cyclamate, cilamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint, neohesperidin DC, neotame, orange , pear, peach, peppermint, cream of mint, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, mint, cream of mint, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame , acesulfame potassium, mannitol, talin, silitol, sucralose, sorbitol, Swiss cream, tagatose, mandarin, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, pear, xylitol, or any combination of these flavoring ingredients, e.g. menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof. Flavorings can be used individually or in combination of two or more. In some embodiments, the aqueous liquid dispersion contains a sweetener or flavoring agent at a concentration of from about 0.001% to about 5.0% by volume of the aqueous dispersion. In one embodiment, the aqueous liquid dispersion contains a sweetener or flavoring agent at a concentration of from about 0.001% to about 1.0% by volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion contains a sweetener or flavoring agent at a concentration of from about 0.005% to about 0.5% by volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion contains a sweetener or flavoring agent at a concentration of from about 0.01% to about 1.0% by volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion contains a sweetener or flavoring agent at a concentration of from about 0.01% to about 0.5% by volume of the aqueous dispersion.

[00687] In certain embodiments, a pharmaceutical composition for pediatric patients described herein includes one or more compounds described herein as an active ingredient in free acid or free base form or in pharmaceutically acceptable salt form. In some embodiments, the compounds described herein are used in N-oxide form or in crystalline or amorphous form (ie, a polymorph). In some situations, the compound described herein exists as tautomers. All tautomers are included within the scope of the compounds presented 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 presented herein are also considered to be described herein.

[00688] 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 formula I-VI, and profile properties release 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 to which are incorporated herein by reference in their entirety for all purposes.

[00689] Additionally, in some embodiments, the pharmaceutical compositions described herein for pediatric patients are formulated in a dosage form. Thus, in some embodiments, provided herein is a dosage form containing 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, rapid 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.

[00690] In certain aspects, a composition or composition for pediatric patients containing one or more compounds described herein is administered orally for local delivery of 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 contain the compositions described herein contained in or enclosed in microspheres. In some embodiments, the microspheres include, by way of non-limiting example, HPMC chitosan microporous capsules and cellulose acetate butyrate (CAB) microspheres. In some embodiments, oral dosage forms are prepared using conventional methods known to those skilled in the pharmaceutical art. For example, in some embodiments, tablets are manufactured using standard tablet processing procedures and equipment. An exemplary tablet forming method is direct compression of a powder, 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, the tablets are molded rather than compressed starting from a wet or pliable material.

[00691] In some embodiments, tablets formulated for oral administration contain various excipients, including, but not limited to, binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents , flavorings, etc. In some embodiments, binders are used to impart cohesive properties to the tablet to ensure that the tablet remains intact after compression. Suitable binders include, by way of non-limiting example, 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, for example, sodium alginate gum, polyvinylpyrrolidone, cellulose polymers (including hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, etc.), vigum and combinations thereof. In certain embodiments, diluents are used to increase the volume of the tablet so that a tablet of practical size is obtained. Suitable diluents include, by way of non-limiting example, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, and combinations thereof. In certain embodiments, lubricants are used to facilitate tablet manufacturing; Examples of suitable lubricants include, but are not limited to, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn and cocoa butter, glycerin, magnesium stearate, calcium stearate, stearic acid, and combinations thereof. In some embodiments, disintegrants are used to facilitate tablet disintegration and include, but are not limited to, starches, clays, celluloses, algins, gums, cross-linked polymers, and combinations thereof. Fillers include, by way of non-limiting example, materials such as silica, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. In some embodiments, stabilizers are used to inhibit or slow drug degradation reactions, which include, for example, oxidative reactions. In some embodiments, the surfactants are anionic, cationic, amphoteric, or nonionic surfactants.

[00692] In some embodiments, ASBTI or other compounds described herein are administered orally in combination with a carrier suitable for delivery to the distal gastrointestinal tract (eg, distal ileum, colon, and/or rectum).

[00693] In certain embodiments, a pediatric 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. intestines and/or colon. In some embodiments, the composition contains a polymer that is pH sensitive (eg, 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, e.g., Carbopol® polymers) that contain acidic groups (e.g. -COOH, -SO ₃ H) and swell at alkaline intestinal pH (eg, 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 (eg, a micronized active agent). In some embodiments, the non-enzymatically degradable lactic-glycolic acid (PLGA) copolymer core is suitable for delivering an enteroendocrine peptide secretagogue to the distal ileum. In some embodiments, the dosage form containing 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) to 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 (eg, D-galactoside, β-D-xylopyranoside conjugates, 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 and the like.

[00694] The pharmaceutical composition described herein for pediatric patients optionally contains an additional therapeutic compound described herein and one or more pharmaceutically acceptable additives, such as a compatible carrier, binder, excipient, suspending agent, flavoring, sweetener, disintegrant, dispersant agent, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration enhancer, wetting agent, defoamer, 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 a composition of a compound of Formula I. In one embodiment, the compound described herein is in particulate form, and some or all of the compound particles contain a coating. In some embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of a compound described herein are not microencapsulated or coated.

[00695] In additional embodiments, a tablet or capsule containing 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, hydroxypropylcellulose, polyethylene glycol 3350, 4500, 8000, methylcellulose, pseudoethylcellulose, amylopectin, and the like. Solid dosage forms for administration to pediatric patients

[00696] Solid dosage forms for administration to pediatric patients of the present invention can be prepared by standard manufacturing methods. Non-limiting examples of oral solid dosage forms for administration to pediatric patients are described below.

Effervescent compositions

[00697] The effervescent compositions of the present invention can be prepared according to techniques well known in the pharmaceutical field.

[00698] Effervescent compositions contain an effervescent pair of a base component and an acid component, the components reacting in the presence of water to form a gas. In some embodiments, the base component may comprise, for example, an alkali or alkaline earth metal carbonate or bicarbonate. The acid 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 constitute, for example, from 25% to 55% (by weight) of the effervescent composition. The ratio of acidic component to basic component can be in the range from 1:2 to 2:1.

[00699] 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. Dyes can also be used, as pediatric patients often prefer colorful pharmaceutical combinations. The compositions may take the form of, for example, tablets, granules or powders, granules or powders presented in sachets.

Chewable tablets

[00700] Chewable tablets of the present invention can be prepared according to techniques well known in the pharmaceutical field.

[00701] 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.

[00702] 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 US Pat. No. 4,647,459, which is incorporated herein by reference in its entirety for all purposes.

[00703] Another approach involves forming the active ingredient into an aggregate together with a pre-swollen, substantially anhydrous hydrocolloid. The hydrocolloid absorbs saliva and develops a slippery texture that helps lubricate the aggregate particles and mask the taste of the active ingredient. This approach is known in the art and is described, for example, in European patent application 0190826, which is incorporated herein by reference in its entirety for all purposes.

[00704] 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 US Pat. No. 5,275,823, which is incorporated herein by reference in its entirety for all purposes.

[00705] In addition to the above approaches, the chewable tablets of the present invention may also contain other standard tabletting aids such as a disintegrant and a taste masking agent.

Orodispersible tablets

[00706] The orodispersible tablets of the present invention can be prepared according to techniques well known in the pharmaceutical field.

[00707] In the orodispersible tablets of the present invention, the mixtures of excipients are such that they provide such a rate of disintegration that its disintegration in the oral cavity occurs in an extremely short time and especially in a period of less than sixty seconds. In some embodiments, the excipient mixture is characterized in that the active substance is in the form of microcrystalline microbeads with or without coating. In some embodiments, the orodispersible tablet contains one or more disintegrants such as carboxymethylcellulose or insoluble cross-linked PVP, one or more swelling agents, which may include carboxymethylcellulose, starch, modified starch or microcrystalline cellulose, or optionally direct compressed sugar.

Powders for dissolution

[00708] The powder for dissolving the pharmaceutical compositions of the present invention can be prepared according to techniques well known in the field of pharmacy.

[00709] In some embodiments, the powder for dissolving the compositions of the present invention contains an effective amount of at least one internal dehydrating agent. An internal dehydrating agent can improve the stability of the powder. In some embodiments, the internal dehydrating agent is magnesium citrate or disodium carbonate. In some embodiments, the powder composition contains pharmaceutically acceptable diluents such as sucrose, dextrose, mannitol, xylitol, or lactose.

[00710] Powder compositions of the present invention can be placed in sachets or vials for simultaneous dissolution or for short-term storage in liquid form (eg, 7 days).

Jelly Bean

[00711] The chewable candies of the present invention can be prepared according to techniques well known in the pharmaceutical field.

[00712] Traditional chewy candies are made with a gelatin base. Gelatin gives candies elasticity, a desirable chewy consistency, and a longer shelf life. In some embodiments, the pharmaceutical chewy candy composition of the present invention includes a binder, a sweetener, and an active ingredient.

[00713] In some embodiments, the binder is a pectin gel, gelatin, food starch, or any combination thereof.

[00714] In some embodiments, the chewy candy contains sweeteners, a binder, natural and/or artificial flavors, colors, and preservatives. In some embodiments, the gummy candy contains glucose syrup, natural cane juice, gelatin, citric acid, lactic acid, natural colors, natural flavors, fractionated coconut oil, and carnauba wax.

Liquid dosage forms

[00715] The pharmaceutical liquid dosage forms of the present invention can be prepared according to techniques well known in the field of pharmacy.

[00716] A solution refers to a liquid pharmaceutical composition in which the active ingredient is dissolved in a liquid. The pharmaceutical solutions of the present invention include syrups and elixirs. Suspension refers to a liquid pharmaceutical formulation in which the active ingredient is present as a sediment in the liquid.

[00717] In a liquid dosage form, it is desirable to have a specific pH value and/or maintain it within a specific pH range. To control the pH, a suitable buffer system can be used. In addition, the buffer system must have sufficient capacity to maintain the desired pH range. Examples of a buffer system used in the present invention include, but are not limited to, nitrate 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. In one embodiment, the concentration is in the range of 0.005 to 0.5% w/v in the final liquid dosage form.

[00718] The pharmaceutical composition containing the liquid dosage form of the present invention may also contain a suspending/stabilizing agent to prevent precipitation of the active material. Over time, settling can cause the active ingredient to cake on the inside walls of the product package, leading to difficulties with redispersing 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) can also be used as a stabilizing agent.

[00719] 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, excipients, acidifiers, enzyme inhibitors and other components, as described in the 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.

[00720] The addition of an alternative solvent may help increase the solubility of the active ingredient in the liquid dosage form and, therefore, absorption and bioavailability in the body of the subject. Preferably, alternative solvents include methanol, ethanol or propylene glycol and the like.

[00721] According to another aspect, the present invention provides a method for preparing a liquid dosage form. The method comprises the steps of admixing ASBTI or pharmaceutically acceptable salts thereof 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, a 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 an aqueous solution to form suspensions.

[00722] In some embodiments, the volume of a liquid dosage form provided herein can be from about 5 ml to about 50 ml. In some embodiments, the volume of a liquid dosage form provided herein can range from about 5 ml to about 40 ml. In some embodiments, the volume of a liquid dosage form provided herein can be from about 5 ml to about 30 ml. In some embodiments, the volume of a liquid dosage form provided herein can be from about 5 ml to about 20 ml. In some embodiments, the volume of a liquid dosage form provided herein can be from about 10 ml to about 30 ml. In some embodiments, the volume of a liquid dosage form provided herein may be approximately 20 ml. In some embodiments, ASBTI may range from about 0.001% to about 90% of the total volume. In some embodiments, ASBTI may range from about 0.01% to about 80% of the total volume. In some embodiments, ASBTI may range from about 0.1% to about 70% of the total volume. In some embodiments, ASBTI may be from about 1% to about 60% of the total volume. In some embodiments, ASBTI may be from about 1% to about 50% of the total volume. In some embodiments, ASBTI may be from about 1% to about 40% of the total volume. In some embodiments, ASBTI may be from about 1% to about 30% of the total volume. In some embodiments, ASBTI may be from about 1% to about 20% of the total volume. In some embodiments, ASBTI may be from about 1% to about 10% of the total volume. In some embodiments, ASBTI may be from about 5% to about 70% of the total volume. In some embodiments, ASBTI may be from about 5% to about 60% of the total volume. In some embodiments, ASBTI may be from about 5% to about 50% of the total volume. In some embodiments, ASBTI may be from about 5% to about 40% of the total volume. In some embodiments, ASBTI may be from about 5% to about 30% of the total volume. In some embodiments, ASBTI may be from about 5% to about 20% of the total volume. In some embodiments, ASBTI may be from about 5% to about 10% of the total volume. In some embodiments, ASBTI may be from about 10% to about 50% of the total volume. In some embodiments, ASBTI may be from about 10% to about 40% of the total volume. In some embodiments, ASBTI may be from about 10% to about 30% of the total volume. In some embodiments, ASBTI may be from about 10% to about 20% of the total volume. In one embodiment, the resulting liquid dosage form may have a liquid volume of from 10 ml to 30 ml, preferably 20 ml, and the active ingredient may be 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 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 approximately 4 mg/ml, or approximately 5 mg/ml, or approximately 8 mg/ml, or approximately 10 mg/ml, or approximately 12 mg/ml, or approximately 14 mg/ml, or approximately 16 mg/ml. Sequester ant bile acids

[00723] In certain embodiments, the oral formulation for use in any method described herein is, for example, 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 (eg, absorbs or absorbs) a bile acid and/or its salts.

[00724] In specific embodiments, a labile bile acid sequestrant is an agent that binds (e.g., absorbs or absorbs) bile acid and/or salts thereof and releases at least a portion of the absorbed or absorbed bile acid and/or salt thereof distally gastrointestinal tract (eg, 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 specific 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 containing pectin, galactomannan and/or azohydrogels and/or glycoside conjugates (eg, D-galactoside, β-D-xylopyranoside conjugates, 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 and the like. In some embodiments, the labile bile acid sequestrant is a time-dependent bile acid sequestrant (ie, the bile acid sequesters the bile acid and/or its salts and releases at least a portion of the bile acid and/or its salts over time). In some embodiments, the time-dependent bile acid sequestrant is an agent that degrades over time in an aqueous environment. In some embodiments, a labile bile acid sequestrant described herein is a bile acid sequestrant that has 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 the environment, where the bile acids/salts and/or their salts are present in high concentration, and release them in an environment in which the bile acids/salts and/or their salts are present in a lower relative concentration. In some embodiments, a 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 salt thereof, followed by release of a secondary bile acid or salt thereof, since the primary bile acid or its salt is converted (eg, metabolized) into a secondary bile acid or its salt. 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 high affinity for bile acid at pH 6 or lower and low affinity for bile acid at pH above 6. In certain embodiments, the pH-dependent bile acid sequestrant degrades at pH above 6.

[00725] In some embodiments, the labile bile acid sequestrants described herein include any compound, such as a macrostructured compound, that can bind bile acids/salts and/or salts thereof through any suitable mechanism. For example, in certain embodiments, bile acid sequestrants sequester bile acids/salts and/or salts thereof through ionic interactions, polar interactions, static interactions, hydrophobic interactions; lipophilic interactions, hydrophilic interactions, steric interactions, etc. In certain embodiments, the macrostructured compounds sequester bile acids/salts and/or sequestrants by trapping the bile acids/salts and/or their salts in pockets of the macrostructured compounds and, optionally, 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 containing any one or more of N-alkenyl moieties -N-alkylamine; 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, or any combination thereof.

Covalent bond between drug and carrier

[00726] In some embodiments, strategies used for colon targeting 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 at achieving colon pH using redox sensitive polymers, using slow release formulations, using coatings that are specifically degraded by colon bacteria, using a bioadhesive system, and using osmotic controlled drug delivery systems.

[00727] In certain embodiments, such oral administration of a composition containing ASBTI or other compounds described herein involves covalent binding to a carrier such that, upon oral administration, the bound moiety remains intact in the stomach and small intestine. Once in the colon, the covalent bond is disrupted due to changes in pH, enzymes, and/or degradation by intestinal microflora. In certain embodiments, the covalent bond between the ASBTI and the carrier includes, by way of non-limiting example, an azo bond, glycosidic conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates, and amino acid conjugates (highly hydrophilic and long-chain carrier amino acids).

Polymer coating: pH sensitive polymers

[00728] In some embodiments, the oral dosage forms described herein are enteric-coated to facilitate delivery of 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 readily dissolves 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 compositions described herein is from about 25 microns to about 200 microns.

[00729] In certain embodiments, the compositions or formulations described herein are coated such that ASBTI or other compounds described herein in the composition or formulation are delivered to the colon and/or rectum without upper intestinal absorption. 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 is slowly degraded until only the core composition containing the enteroendocrine peptide secretagogue (and, in some embodiments, an absorption inhibitor of the agent) remains and the core is delivered to the thick and/or rectum.

[00730] In certain embodiments, pH-dependent systems use a progressively increasing pH along the human gastrointestinal tract (GIT) from the stomach (pH 1-2, which increases to 4 during digestion), small intestine (pH 6-7) in the digestive area and up to 7-8 in the distal ileum. In 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. In certain embodiments, such polymers are capable of withstanding the lower pH of the stomach and proximal small intestine, but disintegrate at neutral or slightly alkaline pH of the terminal ileum and/or ileocecal junction. Thus, in certain embodiments, provided herein is an oral dosage form comprising a coating, wherein the coating comprises a pH-sensitive polymer. In some embodiments, polymers used for targeting the colon and/or rectum include, but are not limited to, 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 ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate 50, hydroxypropyl methyl cellulose phthalate 55, cellulose acetate trimelliate, cellulose acetate phthalate and combinations thereof.

[00731] In certain embodiments, oral dosage forms suitable for delivery to the colon and/or rectum comprise a coating that contains a biodegradable and/or bacterially degradable polymer or polymers that are degradable by microflora (bacteria) in the colon. In such biodegradable systems, suitable polymers include, but are not limited to, azopolymers, segmented linear polyurethanes containing azo groups, polygalactomannans, pectin, glutaraldehyde cross-linked dextran, polysaccharides, amylose, guar gum, pectin, chitosan, inulin, cyclodextrins, chondroitin sulfate, dextrans, locust bean gum, chondroitin sulfate, chitosan, poly(caprolactone), polylactic acid and copolymer of lactic and glycolic acids.

[00732] In certain embodiments of such oral administration of compositions containing one or more ASBTIs or other compounds described herein, the compositions are delivered to the colon without upper intestinal absorption by coating the dosage forms with redox-sensitive polymers, which are decomposed by microflora (bacteria) of the colon. In such biodegradable systems, such polymers include, by way of non-limiting example, redox polymers containing an azo and/or disulfide bond in the backbone.

[00733] 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 the enteroendocrine peptide secretagogues until the dosage form reaches the colon and/or rectum.

[00734] In 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. In certain embodiments, the capsule and hydrogel plug are capped 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 dislodges from the capsule after a period of time and the composition is released from the capsule. The amount of hydrogel is used to control the time period for the release of the contents.

[00735] In 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). In other embodiments, the dosage form is an enteric-coated tablet having an outer shell of hydroxypropylcellulose or hydroxypropylmethylcellulose acetate succinate (HPMCAS).

[00736] According to some embodiments in this document, a oral dosage form is presented, which contains a coating with a floodplain butylulosis fluoride, cellulose hydrofathaft, cellulose popionate, polyvinialcette fluvine, cellulose acetate, cellulose acetate, hydroxypopolia methyl cellulose, hydroxypropylmethyl cellulose hydroxypropylmas, pyoxypropylmethyl cellulose succinate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid and combinations thereof.

Combination therapy

[00737] In some embodiments, the methods provided herein provide for the administration of a compound (eg, 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 (eg, ASBTI) with one or more additional agents.

Fat-soluble vitamins

[00738] In some embodiments, the methods provided herein further comprise the administration of one or more vitamins. In 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, chole calciferol, cyanocobalamin, tocopherols, phylloquinone, menaquinone.

[00739] In some embodiments, the vitamin is a fat-soluble vitamin such as vitamin A, D, E, K, retinol, beta-carotene, cholecalciferol, tocopherols, phylloquinone. In a preferred embodiment, the fat-soluble vitamin is tocopherol polyethylene glycol succinate (TPGS).

Partial external biliary diversion (PEBD)

[00740] In some embodiments, the methods provided herein further provide for the use of partial external biliary diversion as a treatment for patients who have not yet developed 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.

[00741] This surgical method involves isolating a 10 cm long segment of intestine for use as a bile duct (a channel for the passage of bile) from the rest of the intestine. One end of the canal 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 types of drug therapy, especially older and larger patients. This procedure may not help small patients, such as infants. Partial external biliary diversion can reduce the intensity of itching and abnormally low blood cholesterol levels.

ASBTI and PPAR agonists

[00742] In various embodiments, the present invention provides methods of using combinations of ASBTI 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, tesaglitazar, saroglitazar, GW501516, GW-9662, a thiazolidinedione (TZD), an NSAID (eg, IBUPROFEN), indole, or various combinations thereof.

ASBTI and FXR drugs

[00743] In various embodiments, the present invention provides methods for using combinations of ASBTI with drugs targeting the farnesoid X receptor (FXR). In various embodiments, the FXR-targeting drug is avermectin B1a, 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

[00744] In some embodiments, 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 thereof or any combination thereof.

[00745] In 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. In certain embodiments, the patient is administered ursodiol at a daily dose of approximately 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. In various embodiments, the patient is administered ursodiol at 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, from about 1000 mg to about 2000 mg, or from about 1500 to about 1900 mg.

[00746] In various embodiments, ursodiol is administered in tablet form. 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 approximately 60 mg/ml. In various embodiments, the concentration of ursodiol in the suspension is about or is 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. In 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.

[00747] 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 use of a combination of ASBTI and another active ingredient (eg, ursodiol), each of which is administered in a therapeutically effective amount, or due to additive or synergistic effects resulting from combined use, each of which may also be used in a subclinical therapeutic manner. effective amount, i.e. in an amount that, if used alone, provides reduced effectiveness for the therapeutic purposes specified herein, provided that the combined use is therapeutically effective. In some embodiments, the use of a combination of ASBTI and any other active ingredient as described herein includes combinations in which ASBTI or the other active ingredient is present in a therapeutically effective amount and the other is present in a subclinical therapeutically effective amount, provided that combined use is therapeutically effective due to their additive or synergistic effects. As used herein, the term “additive effect” describes the combined effect of two (or more) pharmaceutically active agents that is equal to the sum of the effect of each agent given separately. 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 separately. 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.

[00748] In some embodiments, the specific selection 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 (eg, simultaneously, substantially simultaneously, or as part of the same treatment protocol) or sequentially, depending on the nature of the disease, disorder or condition, the condition of the individual, and the actual choice of compounds used. In some cases, the determination of the order of administration and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based on an assessment of the disease being treated and the condition of the individual.

[00749] 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.

[00750] In some embodiments of the combination therapies described herein, the dosages of the co-administered compounds vary depending on the type of drug used together, the specific drug used, the disease or condition being treated, and so on. In addition, 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 attending physician will decide on the appropriate sequence of the therapeutic compound described herein in combination with an additional therapeutic agent.

[00751] Multiple therapeutic agents (at least one of which is a therapeutic compound described herein) are not necessarily administered in any order or even simultaneously. If concurrently, multiple therapeutic agents are not necessarily provided in one unitary 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 not necessarily administered in multiple doses. In other cases, both are optionally administered in multiple doses. If not simultaneously, the time between multiple doses is any appropriate time; for example, more than zero to less than four weeks. In addition, combination methods, compositions and formulations should not be limited to the use of only two agents; the use of multiple therapeutic combinations (including two or more compounds described herein) is also contemplated.

[00752] In certain embodiments, the dosage regimen for treating, preventing, or ameliorating the condition(s) for 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, sex, diet and medical condition of the subject. Thus, in various embodiments, the dosage regimen actually employed varies and deviates from the dosage regimens set forth herein.

[00753] In some embodiments, the pharmaceutical agents comprising a 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 schedule requiring two-step administration. In some embodiments, a two-step administration regimen requires sequential administration of the active agents or separate administration of 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.

[00754] In certain embodiments, combination therapies are provided herein. In certain embodiments, the compositions described herein contain an additional therapeutic agent. In some embodiments, the methods described herein provide for the administration of a second dosage form containing an additional therapeutic agent. In certain embodiments of the combination therapy, the compositions described herein are administered as part of a regimen. Therefore, additional therapeutic agents and/or additional pharmaceutical dosage form may be administered to a patient directly or indirectly, simultaneously or sequentially with the compositions and formulations described herein.

Sets

[00755] In another aspect, provided herein are kits comprising a rectal administration device pre-filled with a pharmaceutical composition described herein. In certain embodiments, the kits comprise an oral administration device and a pharmaceutical composition described herein. In some embodiments, the kits include a prefilled pouch or bottle for oral administration, while in other embodiments, the kits include prefilled pouches for administering rectal gels. In certain embodiments, the kits include prefilled syringes for administering oral solutions, while in other embodiments, the kits include prefilled syringes for administering rectal gels. In some embodiments, the kits contain prefilled pressurized cans for administering rectal foams.

Release in the distal ileum and/or colon

[00756] In certain embodiments, the dosage form comprises a matrix (eg, a hypermellose-containing matrix) that provides controlled release of the active agent in the distal jejunum, proximal ileum, distal ileum, and/or colon. In some embodiments, the dosage form comprises a polymer that is pH sensitive (eg, 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, e.g., Carbopol® polymers) that contain acidic groups (e.g. -COOH, -SO ₃ H) and swell to an alkaline intestinal pH (eg, pH of about 7 to about 8). In some embodiments, the dosage form suitable for controlled release in the distal ileum contains the active agent in microparticulate form (eg, micronized active agent). In some embodiments, a non-enzymatic lactic-glycolic acid (PLGA) core is suitable for delivering ASBTI to the distal ileum. In some embodiments, the dosage form containing ASBTI is coated with an enteric polymer (e.g., Eudragit® S-100, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic methacrylic acid polymers, methacrylic acid esters, etc.) to 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 containing pectin, galactomannan and/or azohydrogels and/or glycoside conjugates (eg, D-galactoside, β-O-xylopyranoside conjugates, 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 and the like.

[00757] 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, excipient, suspending agent, flavoring, sweetener , disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration enhancer, wetting agent, defoamer, 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 applied around the ASBTI composition. In one embodiment, a compound described herein is in particle form, and some or all of the particles of the compound are coated. In some embodiments, some or all of the particles of a compound described herein are microencapsulated. In some embodiments, the particles of a compound described herein are not microencapsulated or coated.

[00758] An ASBT inhibitor can be used in the formulation 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 may comprise administering pharmaceutical compositions containing at least one ASBT inhibitor described herein, or a pharmaceutically acceptable salt, a pharmaceutically acceptable N-oxide, a pharmaceutically acceptable its active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate in therapeutically effective amounts for the specified individual.

EXAMPLES

[00759] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to be illustrative and not limiting of the disclosed embodiments.

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

[00760] The dosing regimen used in the INDIGO clinical trial is summarized in FIG. 2. In addition to the doses indicated in FIG. 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 dosage was increased to 280 μg/kg QD over 8 weeks.

[00761] The main inclusion criteria for the INDIGO clinical trial were: 1) age from 1 to 18 years; 2) clinical diagnosis of PFIC; 3) two mutant alleles ABCB11 or ATB8B1. The main exclusion criteria for the INDIGO clinical trial were: 1) surgical disruption of the enterohepatic circulation; 2) liver transplantation; 3) decompensated cirrhosis of the liver.

[00762] The following biomarkers of cholestasis were monitored in the INDIGO clinical trial, among others: serum bile acid (sBA) concentrations; serum alanine aminotransferase (ALT) concentration; serum aspartate aminotransferase (ALT) concentration; serum bilirubin concentration and serum 7αC4 concentration. Fecal bile acid (fBA) concentrations were also measured. Itch severity was assessed throughout the INDIGO clinical trial using average weekly observer-reported scratch scores (ITCHRO(OBS)) (a parent-reported electronic diary) and the Clinical Scratch Scale (CSS) (as assessed by the investigator). Patients were also assessed for health-related quality of life (HRQoL) throughout the INDIGO clinical trial. The HRQoL used was the Pediatric Patient Quality of Life (PedsQL) test. Multivariable response was defined as a greater than 70% decrease or normalization of sBA concentration and a greater than 1.0 or less than 1.0 decrease in ITCHRO(OBS).

[00763] 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 ABCB11 non-truncating mutations (classified as mild or moderate) and 6 participants had ABCB11 truncating mutations, see Tables 2-3 and 5. 29 participants reached week 48. see Table 4. Mild PFIC 2 was defined as PFIC 2 resulting from the E297G or D482G mutation of the ABCB11 gene, while moderate PFIC 2 was defined as PFIC 2 resulting from the ABCB11 gene containing a missense mutation but did not contain the E297G or D482G mutation, see Table 3. 19 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), had mild PFIC 2, was a multivariable responder patient in the INDIGO 280 mcg/kg QD clinical trial, see Tables 3, 4, and 6. One patient (1 of 12 patients with mild PFIC 2) PFIC 2), suffering from moderate PFIC 2, demonstrated a response (high-dose responding patient) only after administration of a dose of 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) responded to treatment in the INDIGO clinical trial at a dose of 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 were not multivariate responders in the INDIGO clinical trial, see Tables 3, 5 and FIG. 5.

[00764] Patients who did not respond in Table 3 did not demonstrate a response over time and at the maximum doses indicated in Table 6. Therefore, patients who did not respond could demonstrate a response if maralixibat was administered at a higher dose. dose or over a longer period.

[00765] Therefore, given the above observations, the patient's response to maralixibate administration was correlated with the patient's genotype. In particular, the INDIGO clinical trial showed an unexpected result: only patients suffering from PFIC 2, caused by a non-truncating mutation of the ABCB11 gene, responded to maralixibat. In addition, it was unexpectedly found that patients with moderate PFIC 2 were more likely to respond to 280 μg/kg/day of maralixibate than patients with mild PFIC 2, see Tables 3 and 5-6.

[00766] Six patients demonstrating a response to maralixibat at a dose of 280 μg/kg/day (low dose responders) demonstrated a decrease in sBA concentration, serum ALT concentration, serum bilirubin concentration, ITCHRO(OBS) score and PEDSQL score and increase in serum 7αC4 (C4) concentration by week 48 of the INDIGO clinical trial, see Table 7. Two of the low-dose responders demonstrated a decrease 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 overview of each of the six low-dose responders to maralixibat is presented in FIG. 3. All low-dose responders demonstrated at least a 2.5-fold increase in C4 levels over baseline within 13 weeks of the first maralixibat administration in the INDIGO clinical trial. All low-dose responders demonstrated the establishment of normalized or only slightly elevated serum ALT, AST, and bilirubin concentrations over time (eg, within 2 to 6 months after the first administration of maralixibat) in the INDIGO clinical trial.

[00767] Gastrointestinal infections have been found to interfere with the therapeutic effect of maralixibat in PFIC 2, see FIG. 3D and 3E. Consequently, gastrointestinal infections may cause otherwise sensitive patients to fail to respond to maralixibat.

[00768] Three patients with PFIC 2 with truncation who did not respond to a dose of 280 μg/kg/day of maralixibat were administered 560 μg/kg/day of maralixibate, and one (mentioned above) responded to a higher dose, see Tables 3 and 6.

[00769] Low-dose responders demonstrated 7αC4 concentrations at 48 weeks that were 14 times baseline (range 3-43). 7αC4 concentrations in non-responders were 1.8 times higher than baseline (range 0.5-6) at 48 weeks. This demonstrates a correlation between the response and increased VA synthesis. The mean change from baseline at week 48 in the ratio of 7αC4 concentration to sBA concentration (7αC4:sBA) for low-dose responders was 1388 times the baseline ratio (range 5-3982), whereas the ratio was 1.9 times greater than the baseline ratio (range 0.43-12) in non-responders. The high-dose responder demonstrated a 7αC4:sBA ratio of 12 times baseline before administration of 560 mcg/kg/day maralixibate, which increased to 1770 times baseline with the higher dose.

[00770] Without being limited to any particular mechanism of action, patients with greater preserved tubular transport (as in patients with mild PFIC 2) may require higher doses of maralixibat to block VA absorption than patients with less preserved tubular transport. Additionally, patients with biochemical benefit (increased 7αC4:sBA ratio) but not clinical response may be rescued with higher doses of maralixibat.

[00771] Another unexpected result was observed in the INDIGO clinical trial. Low-dose responders showed improved growth over baseline, while non-responders did not, see FIG. 4. Growth improvement was measured using the height Z-score and was defined as a positive change in height Z-score from the baseline height Z-score measured before maralixibat administration. In addition, the high-dose responder also experienced an increase in height Z-score following response to sBA treatment.

[00772] Twelve patients participated in the long-term extension of the INDIGO clinical trial. In fig. Figures 5-8 show cholestasis marker measurements taken for all participants in the INDIGO clinical trial over time. The high dose responder was initially given a daily dose of 560 mcg/kg/day (2 equal doses of 280 mcg/kg daily, BID) between days 547 and 638, see FIG. 5A. The high dose responder demonstrated an increase in 7αC4:sBA ratio after administration of the higher dose, see FIG. 8. The low-dose responder demonstrated an increase in sBA concentration, a decrease in serum 7αC4 concentration, and a decrease in the 7αC4:sBA ratio during a long-term extension of a higher dose of maralixibat (280 μg/kg BID) from 640 to 730 days, see FIG. 5A and 6-8. After administration of the higher dose, the sBA concentration decreased, the severity of pruritus decreased, the serum 7αC4 concentration increased, and the 7αC4:sBA ratio increased, see FIG. 5A and 6-8. One low-dose responder demonstrated an increase in sBA during long-term extension and was therefore prescribed a higher dose of maralixibat (280 μg/kg twice daily) between days 820 and 910, see FIG. 6. The degree of itching subsequently decreased, see Fig. 6, and the 7αC4:sBA ratio increased, see FIG. 8.

[00773] In the long-term extension of the INDIGO clinical trial, none of the patients carrying the ABCB11 gene with a truncating mutation responded, see FIG. 5V.

[00774] One non-responder patient showed an initial increase in 7αC4:sBA ratio up to 90 days, which subsequently decreased, see FIG. 8. This non-responder could have demonstrated a response if the non-responder had been given a higher dose of maralixibate (eg, 280 mcg/kg twice daily) prior to withdrawal from the INDIGO clinical trial. An initial increase or spike in the 7αC4:sBA ratio indicates that this patient may have demonstrated a response (ie, clinical response) to maralixibate.

[00775] Responding patients in the INDIGO study maintained response to maralixibat for more than a year and up to or more than 5 years, see FIG. 5-8. Patients with persistent BSEP deficiency demonstrated sustained control of pruritus and cholestasis with maralixibat, see FIG. 5-8. In fig. 5-8 show that the 7αC4:sBA ratio is a good predictor of response to ASBTI.

[00776] Responding patients had genotypes consistent with residual BSEP function, while some non-responding patients had genotypes consistent with complete absence of BSEP function. Example 2: Dose-dependent excretion of fecal bile acids with the apical sodium-dependent bile acid transporter inhibitors maralixibate and volixibate in a phase 1 dose-finding clinical trial (NTC02475317) in overweight and obese adults.

[00777] Multiple oral doses of maralixibat, volixibate, 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 ranging from 25 kg/ ^m2 to 35 kg/ ^m2 . Participants ate a low-fiber diet (<10 mg/day) for 2 days before randomization and during the 7-day treatment period. Measurements of fBA, sBA concentration, and serum 7αC4 concentration (which is a biomarker of bile acid synthesis) were performed before drug administration and on day 7.

[00778] Summary demographic data and baseline fBA for participants administered each drug at each indicated dosage are presented in Table 10. Summary demographic data for all patients participating in the study are also presented in Table 10.

[00779] Of the 84 participants, 50 were randomized to the maralixibat group, 20 to the volixibate group, and 14 to the placebo group, see Table 10. All participants completed the study. The mean baseline fBA excretion ranged from 138 to 240 µM (SD, 92-231) for different doses of maralixibat and from 161 to 263 µM (SD, 130-288) for all doses of volixibate and was 246 µM (SD, 114). for placebo, see Table 10.

[00780] fBA excretion increased in a dose-dependent manner for maralixibat and volixibate, with no significant change for placebo, see FIG. 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 fig. 9. At the 10 mg dose for maralixibat and volixibate, the mean deviation from baseline was 515 µmol (95% confidence interval, 196-835) and 744 µmol (95% confidence interval, 230-1257), respectively, see FIG. 9. At the 20 mg dose for maralixibat and volixibat, the mean deviation from baseline was 532 µmol (95% confidence interval, 60-1005) and 874 µmol (95% confidence interval, 457-1290), respectively, see FIG. 9.

[00781] Mean serum 7αC4 increased with administration of maralixibate or volixibate, with the greatest change observed at the 50 mg BID dose of maralixibate, see FIG. 10.

[00782] No noticeable changes were observed in sBA or 7αC4 with placebo, see FIG. 9-10. Mean baseline sBA levels did not increase with maralixibat or volixibate but increased by 2.6 ng/mL (95% confidence interval 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 doses of volixibate and maralixibat or between maralixibat and volixibate. The only treatment-emergent adverse events occurring in more than 10% of participants were headache and diarrhea.

[00783] The increase in fBA excretion was dose dependent up to the maximum doses of volixibate and maralixibate tested, see FIG. 9. Safety results were consistent across all dose ranges tested and between compounds.

[00784] 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-Line, Open-label, Phase 2a, Proof-of-Concept Study of Maralixib (CAMEQ Clinical Trial; ClinicalTrials.gov: NTC02061540)

[00785] 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.

[00786] Participants were adults aged 18-80 years diagnosed with PSC. The 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 a previous biopsy was performed). 27 adults took part in the study.

[00787] Efficacy was assessed by measuring at baseline and throughout the study sBA concentration, serum 7αC4 concentration (a marker of de novo bile acid synthesis), serum autotaxin concentration, LDL-C concentration, serum total cholesterol concentration, liver enzyme concentrations in serum and severity of skin itching. Pruritus severity was determined by calculating weekly totals of adult itch scores and daily averages (average of the 7-day period). Participants self-reported ITCHRO daily on a scale of 0 to 10 (0 = no itching; 10 = worst itching).

[00788] The baseline mean serum alkaline phosphatase concentration for participants in the CAMEO study was 471.6 U/L (SD, 316.9).

[00789] Outcomes were assessed in the overall study population and in subgroups of participants (A) with any pruritus at baseline or (B) with a daily average ITCHRO score ≥4 of 10 at baseline. Efficacy endpoints were based on change from baseline to week 14 or early termination (ET) and analyzed using paired t tests or Wilcoxon signed rank tests.

[00790] Of the 27 participants enrolled, 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.

[00791] Weekly total ITCHRO scores decreased from baseline by 51% (p=0.0495) overall, 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 FIG. 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 participants experienced a worsening of pruritus of more than 1 point from baseline to week 14. Pruritus decreased in all 6 participants with a baseline ITCHRO score ≥4, see Table 11 and FIG. eleven.

[00792] 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 daily average ITCHRO ≥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 107% in participants with daily average ITCHRO ≥4 at baseline, see FIG. 12.

[00793] In the overall CAMEO clinical trial population, there was a significant decrease in serum autotaxin concentration (-148 ng/mL [SD, 319]; p=0.0462) and serum LCL-C concentration (-16.3 mg/dL [SD, 17.6]; P<0.0001), see Fig. 13. Participants with daily average ITCHRO ≥4 at baseline had a significant reduction in autotaxin, see FIG. 13. There was a decrease in total cholesterol in the overall population (mean change -21.2 mg/dL [SE, 4.90; SD, 25.5]; P=0.0002) and in participants with daily average ITCHRO ≥ 4 at baseline (mean change -32.0 mg/dL [SE, 13.38]; p=0.06).

[00794] 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 in participants in the CAMEO clinical trial were not statistically significant.

[00795] A statistically significant reduction in pruritus and sBA was observed after 14 weeks of treatment with maralixibat in the CAMEO clinical trial, consistent with the proposed mechanism of action of maralixibat, see FIG. 1. Serum autotaxin, a potential marker for cholestatic pruritus, was also statistically significantly improved, see FIG. 13. The mean percentage reduction in pruritus and sBA and autotaxin was greater in participants with daily average ITCHRO ≥4 at baseline than in the overall CAMEO study population, see FIG. 14.

[00796] 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 ASBT inhibition.

[00797] Maralixibat was well tolerated in the CAMEO study and was associated with a decrease in serum VA levels in adults with PSC. In addition, autotaxin levels decreased and pruritus improved significantly compared with BL, with the greatest reduction in those with the worst pruritus at baseline. Example 4: Duration of long-term treatment with maralixib 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 pretreatment period with maralixib 400 mcg/kg/day twice daily day (BID) (ICONIC clinical trial)

[00798] Children aged 1-18 years diagnosed with ALGS and evidence of cholestasis were eligible to participate in the ICONIC clinical trial, see Tables 12-14. During long-term extension, participants with sBA above the upper limit of normal and/or ITCHRO(OBS) >1.5 were eligible for the 400 μg/kg BID dose (all participants received the 400 μg/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 concentration (total sBA) >3 times the upper limit of normal, 2) serum conjugated bilirubin concentration >1 mg/day. dl, 3) fat-soluble vitamin deficiency not otherwise explained, 4) serum gamma-glutamyl transferase concentration >3 times the upper limit of normal, and 3) intractable pruritus that can only be explained by liver disease. Inclusion criteria also included the presence of significant itching, which was defined as an average daily ITCHRO(OBS) score of >2 for 2 consecutive weeks (0 = no itching; 4 = worst itching). Exclusion criteria included surgical compromise of the enterohepatic circulation, liver transplantation, decompensated cirrhosis, or any liver disease other than ALGS.

[00799] sBA responders were defined as patients achieving ≥50% reduction in sBA from baseline at week 12 or week 18. ITCHRO responders were defined as patients who achieved at least a 1-point reduction from baseline in weekly average morning ITCHRO(OBS) scores at week 12 or week 18.

[00800] A summary of the experimental design of the ICONIC clinical trial is presented in FIG. 15. After completion of the 48-week pivotal study at 400 mcg/kg per day (QD), participants could continue long-term treatment with maralixibat at 400 mcg/kg QD (extension portion of the study). In an open-label extension study, the effect of higher doses was examined by increasing the dosage to a maximum of 400 mcg/kg BID in eligible participants.

[00801] Efficacy measures were based on changes from baseline in sBA concentrations, weekly average ITCHRO(OBS) scores (0, none; 4, most severe), CSS scores (0, none; 4 most severe), and clinical scores. xanthoma rating scale (0, none; 4, disabling injury). During the randomized withdrawal period (18–22 weeks), differences between maralixibat and placebo in sBA concentrations and ITCHRO(OBS) scores were assessed. During long-term extension, efficacy assessments were performed every 12 weeks. The ICONIC clinical trial also monitored serum total cholesterol and serum 7αC4 concentrations, among other things.

[00802] SBA was measured using a fully validated liquid chromatography-electrospray ionization-mass-electrospray MS (LC-ESI-MS) method using stable isotope dilution analysis to measure serum concentrations of major bile acids (cholic, chenodeoxycholic, ursodeoxycholic, deoxycholic acid, lithocholic and their corresponding glycine and taurine conjugates). Serum samples were analyzed by the Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center in accordance with SOP No. PATH.CMS.1033. Calibration standards for individual bile acids 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. Intra- and inter-assay measurement uncertainty for individual bile acids was within accepted GLP quality assurance guidelines and was <15% of the coefficient of variation for these QC samples. The lower limit of quantitation of the assay was set at 100 ng/mL, and the uncertainty at this concentration was <20%. The detection limit of the assay was 5 ng/ml. Total sBAs are represented by the sum of individual measured bile acid forms.

[00803] Of the 28 participants who completed the main study (up to week 48), 23 consented to the long-term extension. After 2 years, 15 participants continued in the extension phase with a dose increase to 400 μg/kg BID, see FIG. 15-16. Table 14 presents the baseline characteristics and demographics of long-term extension participants.

[00804] sBA concentrations decreased by 31% (p=0.0005) during the first 18 weeks of treatment with maralixibat 400 μg/kg QD, see FIG. 17–18 and 32. During randomized withdrawal, sBA levels returned to baseline in the placebo group but remained unchanged in the maralixibat groups (least squares mean difference [LS], -114.0; SE, 48.0; p =0.03), see Fig. 17-18 and 32. The reduction in sBA was maintained and continued to improve over an extended period of time, see FIG. 18 and 19. After 191 weeks, sBA levels decreased by approximately 57% from baseline (p=0.0047), see FIG. 19.

[00805] Both serum total cholesterol and serum 7αC4 concentrations showed statistically significant decreases from baseline at weeks 48 and 191, see Table 15. Statistically significant decreases in serum total cholesterol and 7αC4 concentrations serum levels observed at week 49 were maintained until week 191 of the ICONIC clinical trial, see Table 15.

[00806] 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 μg/kg QD, see fig. 20, 23, and 32. During randomized withdrawal, pruritus increased in the placebo group but not in the maralixibat group (mean difference LS, -1.5; SE, 0.3; P=0.0001), see FIG. 20, 21, 23, 25 and 32 and Table 16. At week 191, ITCHRO(OBS) had decreased from baseline (mean change -2.5; SE, 0.2; p<0.0001), see Figure . 22-23. Reduction in itching was also demonstrated by a mean reduction in CSS score at week 191 of 2.4 points (SE, 0.4; P < 0.0001), Fig. 22, and an average 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 FIG. 23 and 24. In addition, CSS scores decreased by more than 1.5 points (final mean approximately 1.5) at an average of 48 weeks for all participants, Fig. 22, and ITCHRO(OBS) scores decreased by an average of more than 1.5 points (final average approximately 0.33) from baseline by week 193, see FIG. 23 and 24. Pruritus control improved over time, with observers reporting minimal or no pruritus on more than 89% of study days across all participants (ITCHRO(OBS)<1) at 98 weeks, see FIG. 21-25.

[00807] The reduction in sBA concentration and severity of itching continued further

improved during extension, see fig. 18-19 and 22-24, and xanthomas continued to be reabsorbed (p<0.05), see Fig. 29. CSS scores continued to improve during 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 Fig. 26-27. Thus, maralixibat improved quality of life.

[00808] Clinical Xanthoma Score decreased by 0.7 points (SE, 0.3; p=0.0285) from baseline in participants in the ICONIC clinical trial at week 19. Clinical Xanthoma Scale scores improved significantly (p<0.01) in all participants by week 48, see FIG. 28. The xanthomas continued to be reabsorbed over a long period of time, see FIG. 29. Thus, maralixibat improved xanthomas.

[00809] Maralixibat was well tolerated during the pivotal study and the extension of the ICONIC clinical trial over three years. The treatment effect lasted for more than 48 weeks. Serum concentrations of GGT, ALT, AST and bilirubin were monitored throughout the ICONIC clinical study, see FIG. thirty.

[00810] The therapeutic benefits of maralixibat in children with ALGS were clinically significant and statistically significant. Continuation of maralixibat treatment after the withdrawal period maintained significantly lower sBA levels and less pruritus than placebo during the randomized, placebo-controlled drug withdrawal 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, 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 for treatment durations of up to 4 years.

[00811] A positive correlation was observed between the decrease in sBA concentration and the decrease in itching severity as measured by the ITCHRO(OBS) scale, see FIG. 31-32 and tables 17-19.

[00812] Height Z-score increased by 0.5 (SE, 0.1; p=0.0027) from baseline in participants in the ICONIC clinical trial, see FIG. 33-34. This corresponds to a statistically significant increase in height growth. Consequently, maralixibat improved growth from baseline in patients suffering from ALGS. Moreover, a further increase in height from baseline was observed when patients (N=15) were administered a dose of maralixibat 400 mcg/kg twice daily after receiving a dose of maralixibat 400 mcg/kg once daily for a period exceeding approximately 40 weeks In addition, further improvements in sBA, pruritus and growth were observed after administration of the higher daily dose compared to the improvements observed with the 400 μg/kg once daily dose of maralixibat, see FIG. 18 and 23. Increases in height were also observed as increases in mass Z-scores, see FIG. 35-36. As with height Z-scores, maralixibate administration caused a dose-dependent increase in weight Z-scores, see FIG. 35-36. Participants administered maralixibat 400 μg/kg twice daily after administration of 400 μg/kg maralixibat once daily for more than 40 weeks showed a greater increase in weight Z-score at 400 μg/kg twice daily than at a dose of 400 μg/kg QD.

[00813] All references cited anywhere in this specification are incorporated herein by reference in their entirety for all purposes.

[00814] Although preferred embodiments of the present invention have been shown and described herein, those skilled in the art will appreciate that such embodiments are presented by way of example only.

[00815] The listing of value ranges herein is simply intended to serve as a shorthand way of referring to each individual value falling within the range and each endpoint, unless otherwise specified herein, and each individual value and endpoint is included in the description. as if it were separately read herein.

[00816] Numerous variations, changes and substitutions will now be apparent to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of 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 therein.

Claims (37)

1. A method of increasing height in a pediatric subject suffering from cholestatic liver disease, comprising administering to the subject an effective amount of ASBTI, where ASBTI is (maralixibat) or a pharmaceutically acceptable alternative salt thereof, wherein ASBTI is administered in an amount of from 140 μg/kg/day to 2000 μg/kg/day. 2. The method of claim 1, wherein the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), biliary atresia, Alagille syndrome (ALGS), intrahepatic cholestasis of pregnancy (ICP), or any cholestatic condition of childhood resulting in , height or weight below normal. 3. Method according to any one of paragraphs. 1, 2, in which cholestatic liver disease is biliary atresia. 4. Method according to any one of paragraphs. 1, 2, in which cholestatic liver disease is PFIC. 5. The method of claim 4, wherein the PFIC is selected from a type 1 PFIC, a type 2 PFIC, and a type 3 PFIC. 6. The method of claim 5, wherein the PFIC is a Type 2 PFIC. 7. The method of claim 6, wherein the subject has the ABCB11 gene with a missense mutation and a non-truncating mutation. 8. Method according to any one of paragraphs. 1, 2, in which cholestatic liver disease is ALGS. 9. Method according to any one of paragraphs. 1, 2, in which cholestatic liver disease is an ICP. 10. Method according to any one of paragraphs. 1-9, in which ASBTI is administered once daily (QD). 11. The method of claim 10, wherein ASBTI is administered in an amount of 140 μg/kg/day to 1400 μg/kg/day. 12. Method according to any one of paragraphs. 1-9, in which ASBTI is administered twice daily (BID). 13. The method of claim 12, wherein ASBTI is administered in an amount of 70 μg/kg to 700 μg/kg per dose. 14. Method according to any one of paragraphs. 1-3, in which the increase in height is measured as an increase in the Z-score of height or weight. 15. The method of claim 14, wherein administration results in an increase in height or weight Z-score of at least 0.1 relative to baseline. 16. The method of claim 15, wherein administration results in an increase in height or weight Z-score of at least 0.25 relative to baseline. 17. Method according to any one of paragraphs. 1-16, in which administration results in increased height for 1 year after the first administration of ASBTI. 18. Method according to any one of paragraphs. 1-17, in which the increase in height or weight Z-score is maintained for a period of up to 20 weeks. 19. The method of claim 18, wherein the increase in height or weight Z-score is maintained for a period of up to 2 years. 20. Method according to any one of paragraphs. 1-19, in which ASBTI administration results in a dose-dependent increase in height or weight Z-score. 21. Method according to any one of paragraphs. 1-20, wherein administration of an ASBTI results in a reduction in a symptom or change in a disease-related laboratory value of cholestatic liver disease that persists for at least 10 weeks. 22. The method of claim 21, wherein the reduction of a symptom or change in a laboratory parameter related to the disease includes a decrease in the concentration of sBA, an increase in the concentration of 7αC4 in serum, an increase in the ratio of the concentration of 7αC4 in serum to the concentration of sBA (7αC4:sBA), a decrease 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. 23. The method according to claim 22, wherein the reduction of a symptom or change in a laboratory parameter related to the disease is determined relative to the initial level. 24. Method according to any one of paragraphs. 1-23, in which administration of ASBTI leads to increased excretion of fBA. 25. The method of claim 24, wherein administration of ASBTI results in a dose-dependent increase in fBA excretion. 26. The method of claim 24 or 25, wherein ASBTI is administered at a dose sufficient to result in at least a 1.5-fold increase in fBA excretion over baseline. 27. Method according to any one of paragraphs. 1-26, in which administration of ASBTI results in an increase in the ratio of serum 7αC4 concentration to sBA concentration (7αC4:sBA). 28. The method of claim 27, wherein 7αC4:sBA is increased from about 2 to about 5000 times the baseline. 29. The method of claim 27 or 28, further comprising administering a second dose of ASBTI, wherein the second dose is greater than the first dose if, after administration of the first dose, ASBTI 7αC4:sBA is not maintained at approximately >2 times the initial ratio. 30. The method of claim 27 or 28, further comprising administering a second dose of ASBTI, wherein the second dose is greater than the first dose if the 7αC4:sBA initially increases to at least >2 times the initial ratio and then begins to decrease to original ratio. 31. The method according to claim 1, wherein ASBTI is administered in an amount of from 280 μg/kg/day to 1400 μg/kg/day. 32. The method according to claim 1, wherein ASBTI is administered in an amount of from 140 μg/kg/day to 1400 μg/kg/day. 33. The method according to claim 1, wherein ASBTI is administered in an amount of from 400 μg/kg/day to 1200 μg/kg/day. 34. The method according to claim 1, wherein ASBTI is administered in an amount of 400 μg/kg/day to 800 μg/kg/day. 35. The method according to claim 1, wherein ASBTI is administered in an amount of from 400 μg/kg/day to 2000 μg/kg/day.