Dataset Information

Safety, pharmacokinetics, and pharmacodynamics of milvexian in healthy Japanese participants.

ABSTRACT: This randomized, double-blind, placebo-controlled, multiple ascending-dose study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of milvexian, an oral small-molecule FXIa inhibitor, in healthy Japanese participants. Participants received oral milvexian daily under fasted (50 mg and 200 mg) or fed conditions (500 mg) or placebo over 14 days; 24 participants (8/cohort: 6 milvexian; 2 placebo) were planned. Due to an unblinding event, participants in one cohort (200 mg daily) were discontinued, and a second cohort enrolled; 32 participants were included in safety and pharmacodynamic analyses, and 24/32 in pharmacokinetic analyses. Milvexian up to 500 mg daily for 14 days was generally well tolerated, with no deaths, serious adverse events, or discontinuations due to adverse events. Milvexian exposure increased between 50-mg and 200-mg doses. Median T_max was similar with 50-mg and 200-mg doses (2.5-3.0 h) and delayed under fed conditions (500 mg, 7.0-8.0 h). Median T_1/2 was similar across doses (8.9-11.9 h). Multiple oral milvexian administrations resulted in concentration-related prolongation of aPTT and decreased FXI clotting activity. Milvexian was generally safe and well tolerated. The pharmacokinetic and pharmacodynamic profile of milvexian demonstrates suitability for further clinical development in Japanese participants.

SUBMITTER: Perera V

PROVIDER: S-EPMC8956633 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Safety, pharmacokinetics, and pharmacodynamics of milvexian in healthy Japanese participants.

Perera Vidya V Wang Zhaoqing Z Lubin Susan S Ueno Takayo T Shiozaki Tomomi T Chen Wei W Xu Xiaohui X Seiffert Dietmar D DeSouza Mary M Murthy Bindu B

Scientific reports 20220325 1

This randomized, double-blind, placebo-controlled, multiple ascending-dose study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of milvexian, an oral small-molecule FXIa inhibitor, in healthy Japanese participants. Participants received oral milvexian daily under fasted (50 mg and 200 mg) or fed conditions (500 mg) or placebo over 14 days; 24 participants (8/cohort: 6 milvexian; 2 placebo) were planned. Due to an unblinding event, participants in one coh ...[more]

PMID: 35338177

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Project description:BackgroundPatients with hepatic impairment receiving antithrombotic agents metabolized primarily through the liver can be at risk for bleeding. Milvexian (BMS-986177/JNJ-70033093) is a small-molecule, active-site inhibitor of activated Factor XI (FXIa). Modulation of FXI may provide systemic anticoagulation without increased risk of clinically significant bleeding.ObjectiveThis open-label study evaluated the effects of mild or moderate hepatic impairment on the pharmacokinetics of milvexian to assess their impact on safety and dosing.MethodsSingle doses of milvexian 60 mg were administered to participants with mild hepatic impairment (n = 9), moderate hepatic impairment (n = 8), and normal hepatic function (n = 9). Healthy participants were matched to participants with hepatic impairment by body weight, age, and sex. Analysis of variance was performed on natural log-transformed milvexian exposure parameters, with hepatic function group as a fixed effect.ResultsSingle doses of milvexian 60 mg were generally well tolerated, with no serious adverse events (AEs), bleeding AEs, or discontinuations due to AEs. Geometric mean ratios (90% confidence interval) for total milvexian maximum observed plasma concentration and area under the plasma concentration-time curve from time zero extrapolated to infinite time were 1.180 (0.735-1.895) and 1.168 (0.725-1.882), respectively, for mild hepatic impairment versus normal hepatic function and 1.140 (0.699-1.857) and 0.996 (0.609-1.628), respectively, for moderate hepatic impairment versus normal hepatic function. Across groups, milvexian exposure-related increases were observed for activated partial thromboplastin time.ConclusionMilvexian was well tolerated in participants with normal, mildly impaired, and moderately impaired hepatic function. Observed pharmacokinetic changes suggest it is unlikely that dose adjustments will be necessary in patients with mild or moderate hepatic impairment. Clinical Trial RegistrationClinicaltrials.gov identifier: NCT02982707.

Dataset Information

Safety, pharmacokinetics, and pharmacodynamics of milvexian in healthy Japanese participants.

Publications

Safety, pharmacokinetics, and pharmacodynamics of milvexian in healthy Japanese participants.

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