Single-Dose Pharmacokinetics of Milvexian in Participants with Mild or Moderate Hepatic Impairment Compared with Healthy Participants

Abstract

Background: Patients 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.

Objective: This 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.

Methods: Single 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.

Results: Single 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.

Conclusion: Milvexian 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.

Conflict of interest statement

VP, GA, DL, ZW, SL, WC, AB, and BM are full-time employees of Bristol Myers Squibb. LZ is a full-time employee of Janssen Research & Development, LLC.

© 2022. The Author(s).

Figures

Fig 1

Study design

Fig 2

Mean (± standard deviation) plasma (a) total and (b) unbound milvexian concentration versus time profiles

Fig 3

Effects of hepatic impairment on (a) total and (b) unbound milvexian pharmacokinetic properties. AUC(0–t) area under the plasma concentration–time curve from time zero to the time of last quantifiable concentration, AUC(INF) area under the plasma concentration–time curve from time zero extrapolated to infinite time, CI confidence interval, Cmax maximum observed plasma concentration, fu fraction unbound

Fig 4

Mean (± standard deviation) (a) aPTT and (b) FXIc profile over time for milvexian. aPTT activated partial thromboplastin time, FXIc Factor XI clotting activity

Fig 5

Percentage change from baseline in (a) aPTT and (b) FXIc versus plasma concentrations of milvexian. aPTT activated partial thromboplastin time, FXIc Factor XI clotting activity