Clinical pharmacology in drug development
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Clin Pharmacol Drug Dev · Sep 2018
Randomized Controlled Trial Comparative StudyPharmacokinetics and Safety of Mavatrep (JNJ-39439335), a TRPV1 Antagonist in Healthy Japanese and Caucasian Men: A Double-Blind, Randomized, Placebo-Controlled, Sequential-Group Phase 1 Study.
This single-center, double-blind, placebo-controlled, sequential-group phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of mavatrep (JNJ-39439335), a transient receptor potential vanilloid 1 antagonist, in healthy Japanese and caucasian subjects. In part 1, a single-ascending-dose study, 50 subjects (25 each healthy Japanese and caucasians) were enrolled and received a single oral dose of 10, 25, or 50 mg mavatrep. Caucasian subjects were matched to Japanese subjects with respect to age (±5 years) and body mass index (±5 kg/m2 ). ⋯ After single and multiple dosing, mavatrep was well tolerated. The most common adverse events observed were thermohypoesthesia, feeling cold, chills, and feeling hot. Mavatrep and its metabolites exhibited similar PK profiles after single ascending doses in healthy Japanese and caucasian men.
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Clin Pharmacol Drug Dev · Sep 2018
Randomized Controlled TrialEvaluation of Eluxadoline Effect on Cardiac Repolarization.
This study evaluated the effects of eluxadoline, a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, on cardiac repolarization. This evaluator-blinded, placebo- and positive-controlled, 4-period crossover study randomized healthy men and women to single oral doses of eluxadoline (therapeutic dose 100 mg or supratherapeutic dose 1000 mg), moxifloxacin 400 mg, or placebo. QT data were corrected using individual custom correction (QTcI). ⋯ There were no significant gender effects on ΔΔQTcI values. The most common adverse events were contact dermatitis and nausea (12.5% each) and dizziness (10.9%); adverse events were more frequent in the eluxadoline 1000 mg group. In conclusion, eluxadoline, at therapeutic or supratherapeutic doses, did not significantly prolong QT intervals, and was safe and generally well tolerated in this study population.
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Clin Pharmacol Drug Dev · May 2018
Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.
Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast. ⋯ After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax , AUCinf , and terminal half-life were 1.0 ± 0.32 μg/mL, 12.6 ± 5.4 μg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.
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Clin Pharmacol Drug Dev · May 2017
Randomized Controlled TrialAnalgesic Efficacy of a New Immediate-Release/Extended-Release Formulation of Ibuprofen: Results From Single- and Multiple-Dose Postsurgical Dental Pain Studies.
Analgesic effects of ibuprofen immediate-release/extended-release (IR/ER) 600-mg tablets were evaluated in 2 randomized, double-blind, placebo-controlled dental pain studies. Patients 16-40 years old with moderate-severe pain following third-molar extraction received single-dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). ⋯ Gastrointestinal adverse events predominated with placebo both after study medication administration and after rescue medication use, if applicable. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses.
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Clin Pharmacol Drug Dev · Mar 2016
Effects of Renal Impairment and Hepatic Impairment on the Pharmacokinetics of Hydrocodone After Administration of a Hydrocodone Extended-Release Tablet Formulated With Abuse-Deterrence Technology.
Two open-label, single-dose, parallel-group studies assessed effects of renal and hepatic impairment on the pharmacokinetics of a hydrocodone extended-release (ER) formulation developed with the CIMA Abuse-Deterrence Technology platform. Forty-eight subjects with normal renal function or varying degrees of renal impairment received hydrocodone ER 45 mg (study 1); 16 subjects with normal hepatic function or moderate hepatic impairment received hydrocodone ER 15 mg (study 2). Blood samples were obtained predose and through 144 hours postdose. ⋯ Mean Cmax with normal hepatic function and moderate impairment was 10.1 and 13.0 ng/mL, and mean AUC0-∞ was 155 and 269 ng·h/mL, respectively. Incidence of adverse events was 38% in both groups. Altered systemic exposure in renally or hepatically impaired populations (up to ∼70% higher) should be considered when titrating to an effective dose of hydrocodone ER.