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Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine... more
Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors.Experimental Design: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted.Results: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n = 8). Dose-limiting toxicities were observed a...
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PDF file - 58K, Changes in plasma sVEGFR2 over time in BID cohorts
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ObjectiveTo evaluate potential drug–drug interactions of ubrogepant and atogepant.BackgroundUbrogepant and atogepant, calcitonin gene‐related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive... more
ObjectiveTo evaluate potential drug–drug interactions of ubrogepant and atogepant.BackgroundUbrogepant and atogepant, calcitonin gene‐related peptide (CGRP) receptor antagonists, are recently approved drugs for acute and preventive treatment of migraine, respectively. For patients with migraine who are prescribed atogepant for the preventive treatment of migraine, health care providers could prescribe ubrogepant for the acute treatment of breakthrough migraine attacks.MethodsA phase Ib, multi‐center, open‐label, fixed‐sequence study was conducted in participants diagnosed with migraine for at least 1 year. To assess the primary objective of pharmacokinetic interactions in this phase I trial, the highest United States Food and Drug Administration‐approved individual dose strengths of atogepant (60 mg once daily) and ubrogepant (100 mg) were utilized, with ubrogepant being administered on a fixed‐dose schedule every 3 days, regardless of whether a participant was experiencing a migrai...
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Background:Ubrogepant is metabolized by cytochrome P450 3A4 (CYP3A4) and is a P-glycoprotein (P-gp) substrate.Objective:To assess effects of multiple-dose moderate-strong CYP3A4 and strong P-gp inhibitors and inducers on ubrogepant... more
Background:Ubrogepant is metabolized by cytochrome P450 3A4 (CYP3A4) and is a P-glycoprotein (P-gp) substrate.Objective:To assess effects of multiple-dose moderate-strong CYP3A4 and strong P-gp inhibitors and inducers on ubrogepant pharmacokinetic (PK) parameters.Methods:Two phase 1, open-label, fixed-sequence, single-center, crossover trials enrolled healthy adults to receive ubrogepant 20 mg with/without verapamil 240 mg (a moderate CYP3A4 inhibitor) or ketoconazole 400 mg (a strong CYP3A4 and P-gp transporter inhibitor) (Study A), or ubrogepant 100 mg with/without rifampin 600 mg (a strong CYP3A4 inducer and P-gp inducer) (Study B). Outcomes included ubrogepant PK parameters (area under plasma concentration-time curve, time 0 through infinity [AUC0-∞], peak plasma concentration [Cmax]), and safety (treatment-emergent adverse events [TEAEs]). PK parameters were compared between ubrogepant with/without coadministered medications using linear mixed-effects models. Cmaxand AUC0-∞leas...
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Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the treatment of acute migraine headaches. Ubrogepant demonstrated efficacy and safety in 2 pivotal phase 3 studies (N = 2240) that led to its... more
Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the treatment of acute migraine headaches. Ubrogepant demonstrated efficacy and safety in 2 pivotal phase 3 studies (N = 2240) that led to its approval. Here, we report the pharmacokinetics and safety results from a phase 1 study in which participants with severe (n = 4), moderate (n = 8), or mild (n = 8) hepatic impairment and matched participants with normal hepatic function (n = 8) were administered a single dose of 100 mg of ubrogepant. Twenty‐eight participants aged 36 to 70 years were enrolled and completed the study. In participants with mild, moderate, or severe hepatic impairment, ubrogepant systemic exposure (area under the plasma concentration–time curve) increased by 7%, 52%, and 115%, respectively, compared with participants with normal hepatic function (≈1600 ng • h/mL). Peak exposure increased by 1%, 18%, and 26%, respectively, in participants with mild, moderate, or severe hepatic ...
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N‐methyl‐D‐aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment‐resistant major depressive disorder. This phase... more
N‐methyl‐D‐aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment‐resistant major depressive disorder. This phase I, randomized, multicenter, placebo‐controlled, five‐period, crossover, single‐dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60‐min 100‐km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10‐min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p < ...
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Atogepant is a selective oral calcitonin gene‐related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single‐dose 60 mg atogepant in participants with severe,... more
Atogepant is a selective oral calcitonin gene‐related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single‐dose 60 mg atogepant in participants with severe, moderate, or mild hepatic impairment and matched participants with normal hepatic function from an open‐label, parallel‐group, single‐dose phase 1 trial. Thirty‐two participants aged 45 to 72 years were enrolled, which included 8 each with severe, moderate, mild, or no hepatic impairment. All participants completed the study. Atogepant was rapidly absorbed (median time to maximum plasma concentration, ∼2 hours) with an apparent terminal elimination half‐life of ∼11 hours. Compared with participants with normal hepatic function, the change in maximum plasma concentrations of atogepant were –4%, –12%, and +9% in participants with severe, moderate, or mild hepatic impairment, respectively. Overall systemic exposures to atogepant were 15% to 38% higher in ...
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INTRODUCTION: MD-7246 is a delayed-release formulation of linaclotide (LIN), releasing drug in the distal ileum, under development for treating visceral pain with limited pro-secretory effects. LIN, a GC-C agonist, is approved as an... more
INTRODUCTION: MD-7246 is a delayed-release formulation of linaclotide (LIN), releasing drug in the distal ileum, under development for treating visceral pain with limited pro-secretory effects. LIN, a GC-C agonist, is approved as an immediate-release (IR) formulation, releasing in the stomach, for treating irritable bowel syndrome with constipation and chronic idiopathic constipation. This study assessed the safety, tolerability, and pharmacokinetics of MD-7246 and explored select pharmacodynamic (PD) parameters. METHODS: This double-blind, placebo-controlled study randomized healthy adult volunteers to placebo or 1 of 3 daily doses of MD-7246 for 7 days. Safety and tolerability were assessed at each dose prior to dose escalation. PD assessments for spontaneous bowel movement [SBM]/week and stool consistency (Bristol stool form scale [BSFS]) were recorded in a diary. RESULTS: Placebo, low, mid, or high doses of MD-7246 were received by 6 subjects each. Neither LIN nor its active met...
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Formulations of neutral retinoids, in particular fenretinide (HPR) in the form of lipid nanoparticles, solid dispersions and emulsions are disclosed. These compositions are used to treat diseases that are amenable to treatment by HPR,... more
Formulations of neutral retinoids, in particular fenretinide (HPR) in the form of lipid nanoparticles, solid dispersions and emulsions are disclosed. These compositions are used to treat diseases that are amenable to treatment by HPR, such as neoplastic diseases by achieving higher and more prolonged concentrations of HPR in the subject. The key steps for preparing lipid nanovesicles of HPR include mixing and sonication, sterile filtration, without or without lyophilization for long-term stable storage, and employ processes and materials that are scalable from the laboratory to the manufacturing level. The formulation are suitable for injection into human or animal patients without causing allergic or hypersensitivity responses by avoiding chemical surfactants and animal sources of phospholipids in their manufacture.
The time-dependent influence of pentoxifylline (PTX) on the pharmacokinetics of carbamazepine (CBZ) was studied after single-dose oral administration of 100 mg CBZ either alone or in combination with 400 mg PTX at 10:00 and 22:00 h. Serum... more
The time-dependent influence of pentoxifylline (PTX) on the pharmacokinetics of carbamazepine (CBZ) was studied after single-dose oral administration of 100 mg CBZ either alone or in combination with 400 mg PTX at 10:00 and 22:00 h. Serum samples were collected at predetermined time intervals and analysed for unchanged CBZ using high-performance liquid chromatography. The pharmacokinetic parameters of CBZ were calculated using the model-independent method. PTX reduced the rate (Tmax, 8.58 +/- 2.64 vs 5.66 +/- 1.44 h; K(a); 0.47 +/- 0.14 vs 0.72 +/- 0.19 h(-1)), but not the extent of CBZ absorption at 22:00 h treatment. However, such a change was not observed for 10:00 h treatment. No significant changes were observed in other pharmacokinetic parameters of CBZ under the influence of PTX for both 10:00 h as well as 22:00 h treatments. The clinical significance of the time-dependent influence of PTX on the rate of absorption of CBZ will be revealed upon extension of the study to patients.
Research Interests: Pharmacology, Chemistry, Pharmacokinetics, Drug interactions, Enzyme Inhibitors, and 13 moreMedicine, Humans, Calibration, Male, High Performance Liquid Chromatography, Adult, Carbamazepine, Time Dependent, Time Factors, Pharmacological, Human Subjects, Pentoxifylline, and Pharmacology and pharmaceutical sciences
In most Wuchereria bancrofti and Brugia malayi infections, the microfilaria are found in the blood in greatest number between 10 p.m. and 2 a.m., indicating that chronotherapy may be beneficial in treating such infections. This study... more
In most Wuchereria bancrofti and Brugia malayi infections, the microfilaria are found in the blood in greatest number between 10 p.m. and 2 a.m., indicating that chronotherapy may be beneficial in treating such infections. This study reports the influence of time of administration on the pharmacokinetics of diethylcarbamazine (DEC) in healthy volunteers. The study was conducted in 12 healthy volunteers by administering a 150 mg single oral dose of diethylcarbamazine citrate at 0600 or 1800 h in a balanced crossover design with the approval of an institutional ethics committee. The subjects fasted for about 10 hours before and 3 hours after drug treatment. Blood samples were collected at predetermined time intervals, and the drug content in the serum was estimated using HPLC with an electrochemical detector. Pharmacokinetic analysis was performed using noncompartmental methods employing WinNonlin (version 3.1), and the means of various pharmacokinetic parameters were compared for any...
Research Interests: Pharmacokinetics, Clinical Pharmacology, Medicine, Humans, Lymphatic Filariasis, and 13 moreBlood sampling, Adult, Human Subjects, Cross-Over Studies, Chronotherapy, Area Under Curve, DIETHYLCARBAMAZINE, Drug treatment, Wuchereria bancrofti , Dosing, Pharmacology and pharmaceutical sciences, crossover study, and Time of day
Vilazodone is a potent serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder (MDD) in adults. The effect of clinical and supratherapeutic doses of vilazodone on cardiac... more
Vilazodone is a potent serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder (MDD) in adults. The effect of clinical and supratherapeutic doses of vilazodone on cardiac repolarization was determined in healthy volunteers. In this Phase 1, randomized, doubleblind, placebo- and active-controlled, 3-arm, parallel, single-center study, healthy subjects received placebo; moxifloxacin 400 mg; or vilazodone (sequentially escalated every 3 days) 10, 20, 40, 60, and 80 mg/day. The primary endpoint was the time-matched change from baseline in the QT interval corrected for heart rate (QTc) using an individual correction method (QTcI). Placebo-corrected time-matched analysis of the QTcI duration for the vilazodone treatment effect indicated that no vilazodone dose had an upper bound that approached or exceeded 10 ms, demonstrating no signal for a significant vilazodone effect on cardiac repolarization. Vilazodone had no significant effect on heart rate, PR, or QRS interval duration. The pharmacokinetic/pharmacodynamic model showed that the QTcI slope for vilazodone was not different from 0.0 and that the predicted increase from baseline in the QTc at Cmax for the highest therapeutic dose (156 ng/ml after 40 mg/day) was &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 1 ms. The incidence of adverse events (AEs) was higher in the vilazodone group (57.6%) than in the moxifloxacin (37.0%) and placebo (35.6%) groups, though AEs were generally mild to moderate in severity and resulted in few discontinuations. Vilazodone had no significant effect on cardiac repolarization, heart rate, PR or QRS interval duration, or ECG morphology in healthy adult participants.
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Research Interests: Chemistry, Chromatography, Medicine, Dosage Form, Humans, and 14 moreRheumatic Heart Disease, Drug Delivery Systems, Epidermis, European, Topical Drug Administration, Diclofenac, Vesicle, Zeta Potential, Cumulant, Lecithin, Diclofenac Sodium, Transdermal, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Food effects were defined as positive, when coadministration of food causes an increase in the extent of absorption (AUC(0-∞)) of a drug when compared with fasted state drug administration and no effect when coadministration of food... more
Food effects were defined as positive, when coadministration of food causes an increase in the extent of absorption (AUC(0-∞)) of a drug when compared with fasted state drug administration and no effect when coadministration of food causes no change in AUC(0-∞). In general, low solubility drugs exhibit positive food effects due to improved solubility in fed state administration. But, certain high-solubility and high-permeability drugs that undergo extensive presystemic metabolism exhibit positive food effects because of the increased splanchnic hepatic blood flow in the fed state presumably causing a fraction of drug to bypass first-pass metabolism during absorption. In this study, systemic clearance (Cl) of structurally diverse high-permeability and high-solubility drugs was correlated to their food effects to explore whether drugs undergoing low clearance exhibited no food effects and drugs undergoing high clearance exhibited positive food effects. Six drugs exhibiting positive food effects and nine drugs exhibiting no food effects (for comparison) were selected for linear regression analysis. Regression analysis of the selected drugs indicated that percent food effects correlated linearly to Cl and fitted the equation: percent food effects = 0.9163 × Cl - 6.4789. The R(2), p-value and power of the regression model were &amp;amp;amp;amp;amp;amp;amp;amp;gt;0.88, 0.9999, respectively indicating the direct correlation between Cl and food effects of the selected model drugs; other statistical tests validated the model. The model indicated that high-solubility and high-permeability drugs undergoing Cl of more than 27 L/h may exhibit statistically significant positive food effects.
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To determine the oral bioavailability of R-XK469, a water-soluble investigational anticancer agent undergoing phase I clinical trials as an intravenous product. R-XK469 was administered to two groups of catheterized Sprague-Dawley rats... more
To determine the oral bioavailability of R-XK469, a water-soluble investigational anticancer agent undergoing phase I clinical trials as an intravenous product. R-XK469 was administered to two groups of catheterized Sprague-Dawley rats via the oral and IV routes at a dose of 10 mg/kg and blood samples were collected at predetermined times. XK469 in plasma samples was quantified using a HPLC method. The pharmacokinetic parameters were computed using WinNonlin 4.0.1 software. The pharmacokinetic parameters of XK469 following oral and IV administrations, respectively, were (mean+/-SD): C(max) 138+/-64 and 404 +/- 355 microg/ml; AUC(0-infinity) 2381 +/- 773 and 2854 +/- 1924 microg h/ml; and elimination half-life (T(1/2)) 12.9 +/- 5.8 and 13.5 +/- 7.8 h T(max) was 2.92+/-1.92 h following oral dosing. Oral R-XK469 was 83% bioavailable. Together with the antitumor efficacy of oral XK469 shown in preclinical models and its schedule dependency, these results indicate the promise of developing an oral dosage form of R-XK469 for clinical development.
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The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene‒related peptide receptor—in... more
The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene‒related peptide receptor—in development for migraine prevention—is thus likely to be used by women taking oral contraceptives. This phase 1, open‐label, single‐center, 2‐period, fixed‐sequence study examined the effect of multiple‐dose atogepant 60 mg once daily on the single‐dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7‐day washout. In period 2, atogepant was given once daily on days 1‐17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty‐si...
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Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), single-dose rifampin (strong OATP inhibitor)... more
Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), single-dose rifampin (strong OATP inhibitor) and multiple-dose rifampin (strong CYP3A4 inducer) on single-dose pharmacokinetics (PK) and safety of atogepant were assessed. Methods: Two phase I, open-label, single-center, crossover trials enrolled healthy adults. Results: Cmax and area under the curve of atogepant increased when co-administered with itraconazole. Atogepant systemic exposure increased following co-administration with single-dose rifampin. Atogepant systemic exposure decreased with co-administration of multiple-dose rifampin. Treatment emergent adverse events (TEAEs) were predominantly mild or moderate, and included constipation, dizziness, headache and nauseas. Conclusion: Systemic exposure of atogepant increased significantly when co-administered with a strong CYP3A4 or OATP inh...
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Eluxadoline is a mixed μ‐opioid, κ‐opioid receptor agonist, and δ‐opioid receptor antagonist, approved in the United States for adults with diarrhea‐predominant irritable bowel syndrome. This phase 1, single‐center, open‐label,... more
Eluxadoline is a mixed μ‐opioid, κ‐opioid receptor agonist, and δ‐opioid receptor antagonist, approved in the United States for adults with diarrhea‐predominant irritable bowel syndrome. This phase 1, single‐center, open‐label, single‐sequence study was conducted on 30 healthy participants to establish whether steady‐state eluxadoline increases systemic exposure of the cytochrome P450 (CYP) 3A4 substrate midazolam. Participants received oral midazolam 4 mg on day 1 with a 7‐day washout period. On days 8‐16, oral eluxadoline 100 mg was administered twice daily. On day 15, midazolam 4 mg was coadministered with the eluxadoline 100‐mg morning dose. Primary outcome measures were pharmacokinetic parameters of midazolam and 1‐hydroxy‐midazolam. The midazolam and 1‐hydroxy‐midazolam geometric mean ratios and 90%CIs for maximum plasma drug concentration were 99.0% (91.6‐107.0) and 113.8% (104.9‐123.5), respectively, and area under the plasma concentration–time curves were 90.5% (83.9‐97.6) ...
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Supplemental Material, Jakate-et-al_SUPPLEMENTAL-MATERIAL-FOR-SUBMISSION for Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized... more
Supplemental Material, Jakate-et-al_SUPPLEMENTAL-MATERIAL-FOR-SUBMISSION for Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized trial by Abhijeet Jakate, Ramesh Boinpally, Matthew Butler, Kaifeng Lu, Kristi Womack, Danielle McGeeney and Antonia Periclou in Cephalalgia Reports
Atogepant is a selective, oral calcitonin gene–related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double‐blind, phase 1 crossover study evaluated the cardiac repolarization effect of... more
Atogepant is a selective, oral calcitonin gene–related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double‐blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open‐label active control. The primary end point was a change from baseline in Fridericia‐corrected QT intervals (ΔQTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline (ΔΔQTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2‐, 3‐, and 4‐hour time points. Following single‐dose atogepant 300 mg, mean atogepant ΔΔQTcF and upper 90% confidence interval limits were lower than the 10‐millisecond threshold at all time points. Atogepant mean peak pla...
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Ciprofloxacin is routinely prescribed to treat a variety of infections, including those of the urinary tract. To achieve optimum therapeutic benefits of the drug, all of the factors which influence its pharmacokinetics and effectiveness... more
Ciprofloxacin is routinely prescribed to treat a variety of infections, including those of the urinary tract. To achieve optimum therapeutic benefits of the drug, all of the factors which influence its pharmacokinetics and effectiveness need to be determined. This study investigated the urinary excretion kinetics of ciprofloxacin upon oral administration of a single dose of 250 mg at 1000 or 2200 h in 12 healthy human subjects in a crossover design. The urine samples were analyzed for unchanged ciprofloxacin by a sensitive high-performance liquid chromatography method. A significant decrease in the rate and extent of ciprofloxacin excretion following 2200 h (109.59 versus 53.8 mg [P < 0.05]) administration was observed. This result may be due to circadian changes in the factors affecting renal excretion and also probably metabolism of ciprofloxacin.
Research Interests: Pharmacology, Microbiology, Chemistry, Kinetics, Medical Microbiology, and 15 morePharmacokinetics, Medicine, Circadian Rhythm, High Performance Liquid Chromatography, High Speed, Liquid Chromatography, Blood Flow, Antimicrobial agents, Gastrointestinal Tract, Ciprofloxacin, Flow Rate, Human Subjects, excretion, Pharmacology and pharmaceutical sciences, and crossover study
Research Interests: Pharmacology, Pharmacokinetics, Medicine, Humans, Female, and 14 moreMale, Memantine, Bioavailability, Donepezil, Bioequivalence, Adult, Combination drug therapy, Alzheimer Disease, Biological Availability, Cross-Over Studies, Piperidines, Fixed dose combination, Indans, and Pharmacology and pharmaceutical sciences
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Research Interests: Analytical Chemistry, Pharmacokinetics, Medicine, Therapeutic drug monitoring, Humans, and 15 moreFemale, Ovulation, Menstrual Cycle, Bioavailability, High Pressure Liquid Chromatography, Saliva, Adult, Acetaminophen, Biological Availability, Area Under Curve, Follicular phase, Pharmacology and pharmaceutical sciences, crossover study, Luteal phase, and Cmax
Optimization of therapy by chronopharmacology requires knowledge of rhythmic manifestations of disease activity and chronopharmacokinetic data of the drugs prescribed. Rhythmic functioning of the cardiovascular system in healthy and... more
Optimization of therapy by chronopharmacology requires knowledge of rhythmic manifestations of disease activity and chronopharmacokinetic data of the drugs prescribed. Rhythmic functioning of the cardiovascular system in healthy and diseased subjects is manifested as circadian rhythms in blood pressure, cardiac output, heart rate, etc. The disposition of several cardiovascular drugs in man has been reported to be time-dependent. This study reports the effect of time of administration on the disposition of pentoxifylline. Twelve healthy volunteers were treated with 400 mg pentoxifylline orally at 0100, 0700, 1300 and 1900 h in a randomized crossover Latin-square design with a wash-out period of one week. Serum samples were analysed for unchanged pentoxifylline by HPLC. Pharmacokinetic parameters were calculated using a model-independent method. The mean values of various pharmacokinetic parameters after drug treatment at these times were, respectively: maximum plasma concentration (C...
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Purpose Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non–small-cell lung cancer (NSCLC) patients who... more
Purpose Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non–small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg. Patients and Methods Cohorts of NSCLC patients currently smoking ≥ 10 cigarettes per day for ≥ 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity. Results Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance ...
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Research Interests: Gastroenterology, Clinical Trial, Chemotherapy, Medicine, Cell line, and 15 moreRenal Cancer, Humans, Internal Medicine, Female, Renal cell Carcinoma, Male, Aged, Middle Aged, Adult, Bone Metastases, Antineoplastic Agents, Phase II Trial, fenretinide, Pharmacology and pharmaceutical sciences, and Metastatic Renal Cell Carcinoma
Purpose: BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive antitumor activity in preclinical studies including in taxane-resistant models. We conducted a... more
Purpose: BMS-247550 is a semisynthetic derivative of epothilone B with mechanism of action analogous to paclitaxel. It has shown impressive antitumor activity in preclinical studies including in taxane-resistant models. We conducted a phase I trial, based on accelerated titration “2B” design, of BMS-247550 given as a 1-hour infusion every 3 weeks. Experimental Design: Seventeen patients (M:F, 10:7; median age, 54 years; performance status, 0-2) were treated on the trial. Forty-five cycles (1-9 cycles) of BMS-247550 were given at dosages ranging from 7.4 to 56 mg/m2. All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists. Results: First-course dose-limiting toxicity (DLT) was observed in two of three patients at 56 mg/m2 (neutropenic sepsis, prolonged grade 4 neutropenia) and in one of six patients at 40 mg/m2. Nonhematologic grade 3 to 4 toxicities observed were emesis and fatigue and they occurred only at 5...
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Research Interests: Clinical Trial, Treatment Outcome, Prostate Cancer, Medicine, Humans, and 15 moreInternal Medicine, Female, Male, Cancer Chemotherapy, Aged, Middle Aged, Adverse Event, Neoplasms, Antineoplastic Agents, Adverse effect, Breast Neoplasms, Prostatic neoplasms, Pharmacology and pharmaceutical sciences, Urinary bladder neoplasms, and Solid tumor
Research Interests: Cancer, Food, Drug metabolism, Apoptosis, Fasting, and 15 moreFemale, Drug Resistance, Cancer Chemotherapy, Food intake, High Pressure Liquid Chromatography, Aged, Adult, Biological activity, Abdominal Pain, Antineoplastic Agents, Antineoplastic Drugs, Area Under Curve, Cohort Studies, Glycogen Synthase Kinase, and Cmax
Research Interests: Cell Cycle, Cancer Research, Apoptosis, Medicine, Western blotting, and 15 moreMice, Female, Animals, Cell Death, Head and neck squamous cell carcinoma, Clinical Sciences, High Pressure Liquid Chromatography, In Vivo, Western blot, Protein Expression, Head and Neck Surgery, Tumor Growth, Docetaxel, Disease Free Survival, and Head and neck neoplasms
Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or... more
Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration–time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80–1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69–0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80–1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.
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<b>Supplementary Table 1</b>. Atogepant and Sumatriptan: No Clinically Relevant Drug-Drug Interactions in a Randomized, Open-label, Crossover Trial <i>Intervention Sequences</i>
Supplemental Material, sj-pdf-1-rep-10.1177_25158163211037344 for Effects of CYP3A4 and P-glycoprotein inhibition or induction on the pharmacokinetics of ubrogepant in healthy adults: Two phase 1, open-label, fixed-sequence,... more
Supplemental Material, sj-pdf-1-rep-10.1177_25158163211037344 for Effects of CYP3A4 and P-glycoprotein inhibition or induction on the pharmacokinetics of ubrogepant in healthy adults: Two phase 1, open-label, fixed-sequence, single-center, crossover trials by Abhijeet Jakate, Ramesh Boinpally, Matthew Butler, Wendy Ankrom, Marissa F Dockendorf and Antonia Periclou in Cephalalgia Reports
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ObjectiveTo evaluate the impact of two calcitonin gene–related peptide (CGRP)‐targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant.BackgroundPeople... more
ObjectiveTo evaluate the impact of two calcitonin gene–related peptide (CGRP)‐targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant.BackgroundPeople taking CGRP‐targeted mAbs for migraine prevention sometimes take ubrogepant, an oral small‐molecule CGRP receptor antagonist, for acute treatment of breakthrough migraine attacks.DesignIn this two‐arm, multicenter, open‐label, phase 1b trial, adults with migraine were randomized to arm 1 (ubrogepant ± erenumab) or arm 2 (ubrogepant ± galcanezumab). The PK profile of ubrogepant was characterized for administration before and 4 days after CGRP‐targeted mAb injection. Participants received single‐dose ubrogepant 100 mg on day 1, subcutaneous erenumab 140 mg (arm 1) or galcanezumab 240 mg (arm 2) on day 8, and ubrogepant 100 mg once daily on days 12–15. In each study arm, serial blood samples were drawn on days 1 and 12 for measurement of plasma ubrogepa...
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Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for preventive treatment of migraine. To evaluate potential pharmacokinetic drug–drug interactions (DDIs), safety and tolerability of atogepant... more
Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for preventive treatment of migraine. To evaluate potential pharmacokinetic drug–drug interactions (DDIs), safety and tolerability of atogepant co-administered with acetaminophen or naproxen in healthy participants. This open-label, randomized, five-way crossover, single-center, phase 1 DDI trial randomized healthy adult participants to one of ten intervention sequences to receive single-dose 60 mg atogepant, 1000 mg acetaminophen, 500 mg naproxen, or co-administrations of atogepant with acetaminophen or naproxen, with 7-day washout periods between interventions. Potential DDIs were assessed using geometric mean ratios and 90% confidence intervals (CIs) calculated from maximum plasma drug concentrations (Cmax) and area under the plasma drug concentration-time curves (AUCs) for co-administered medications versus medications administered alone. Secondary pharmacokinetic parameters [time to Cmax (tmax), terminal elimination half-life (t1/2), volume of distribution during terminal phase (VZ/F), total body clearance (CL/F)], and safety were evaluated. Forty participants enrolled; 35 (87.5%) completed the trial. Atogepant Cmax was unchanged, AUC0–t and AUC0–∞ both increased 13%, and tmax and t1/2 were unchanged when co-administered with acetaminophen; and acetaminophen Cmax decreased 11%, AUC0–t and AUC0–∞ both decreased 6%, and tmax and t1/2 were unchanged when co-administered with atogepant. Atogepant mean (SD) Vz/F and CL/F were 369.45 (255.68) L and 18.88 (9.28) L/h, respectively, when administered alone and 297.56 (196.01) L and 16.33 (6.11) L/h when co-administered with acetaminophen. Atogepant Cmax was unchanged, AUC0–t and AUC0–∞ both decreased 1%, and tmax and t1/2 were unchanged when co-administered with naproxen; and naproxen Cmax decreased 6%, AUC0–t and AUC0–∞ both decreased 2%, and tmax and t1/2 were unchanged when co-administered with atogepant. Atogepant mean (SD) Vz/F and CL/F were 359.61 (247.99) L and 18.80 (7.78) L/h, respectively, when co-administered with naproxen. Treatment-emergent adverse events (TEAEs) occurred at rates of 5.6–21.1% across interventions. The most commonly reported TEAEs were oropharyngeal pain (n = 2, with atogepant; not treatment related) and nausea (n = 2, with atogepant/acetaminophen; treatment related). Co-administration of 60 mg atogepant with 1000 mg acetaminophen or 500 mg naproxen was safe and well tolerated in healthy participants, and no DDIs were observed.
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as potential risk factors. The current population of studies suffers from risks of publication and design biases, but substantiates that further research is needed. If an association is confirmed, further mechanistic research and targeted... more
as potential risk factors. The current population of studies suffers from risks of publication and design biases, but substantiates that further research is needed. If an association is confirmed, further mechanistic research and targeted psychological therapies development is warranted. These data support the importance of a growing number of adverse health outcomes associated with ACEs and substantiate communityand societal-based interventions to reduce them.
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INTRODUCTION: Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The... more
INTRODUCTION: Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The intention of this study was to evaluate linaclotide's efficacy in relieving IBS-C-related abdominal symptoms (bloating, discomfort, and pain) using a novel multi-item Abdominal Score (AS). METHODS: Patients with IBS-C with abdominal pain ≥3 (0–10 scale) were randomized to linaclotide 290 μg or placebo daily for 12 weeks. The AS, derived from the Diary for IBS Symptoms-Constipation, is the average of abdominal bloating, discomfort, and pain at their worst (0 = none, 10 = worst possible). The primary end point was overall change from baseline (CFB) in AS. Secondary end points included CFB in 12-week AS evaluated using cumulative distribution function and 6-week/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week). RESULTS: Overall, 614 pa...
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Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist approved by the US Food and Drug Administration for acute treatment of migraine with or without aura in adults. Objectives: To assess potential... more
Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist approved by the US Food and Drug Administration for acute treatment of migraine with or without aura in adults. Objectives: To assess potential pharmacokinetic (PK) drug–drug interactions in healthy participants and inform the safety and tolerability of ubrogepant alone and in combination with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy participants and participants with migraine. Methods: Two phase 1, three-way crossover studies randomized healthy adults to 100 mg ubrogepant alone, 1000 mg acetaminophen or 500 mg naproxen alone, and 100 mg ubrogepant plus 1000 mg acetaminophen or 500 mg naproxen. Geometric mean ratios (GMRs) and 90% confidence intervals were calculated based on statistical comparison of maximum plasma drug concentration ( C max) and area under the plasma drug concentration–time curve (AUC) for treatment in combination versus alone. Two phase 3 r...