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.

Single-Dose Pharmacokinetics of Milvexian in Participants with Normal Renal Function and Participants with Moderate or Severe Renal Impairment

“…Bleeding risk in patients receiving currently available anticoagulants is variable [ 46 ], but patients with renal impairment are at a higher risk of bleeding events generally and may benefit from dose adjustments of anticoagulants [ 47 , 48 ]. Safety and tolerability results from the current study of milvexian add to evidence from a phase I study in healthy volunteers as well as a phase I study in participants with hepatic impairment that also demonstrated the safety and tolerability of milvexian [ 31 , 32 ].…”

“…Milvexian is being developed to prevent thrombotic events in diverse patient populations. It has demonstrated antithrombotic activity while preserving hemostasis in preclinical models of arterial and venous thrombosis, and was generally safe and well tolerated in phase I studies in healthy participants and in individuals with hepatic impairment [ 29 – 32 ]. Milvexian is being investigated in an ongoing phase II study for the secondary prevention of major cardiovascular events in patients with acute ischemic stroke [ 33 ].…”

Factor XI, a potential target for anticoagulation therapy for venous thromboembolism

“…FXI inhibitors are not only orally available but also maintain anticoagulant effect for up to 1 month (38,39), which significantly improves patient compliance by eliminating the need for routine monitoring and avoiding the effects of discontinuation or irregular readministration after discontinuation. In addition, FXI inhibitors, regardless of different application strategies, have stable pharmacokinetics, good anticoagulation, and a low incidence of adverse events such as headache and fatigue (37)(38)(39)(40). Therefore, FXI inhibitors are safe, but more studies are needed to observe patients with renal insufficiency, combination dosing, and bridging therapy.…”

“…Recent studies have found that FXII and FXI inhibitors single target of intrinsic coagulation pathway and play a limited role in hemostasis in vivo , thus they have good anticoagulation effect and safety ( 36 ). In addition, FXI inhibitors are metabolized by the liver, but they are tolerated in patients with mild and severe liver damage ( 37 ). FXI inhibitors are not only orally available but also maintain anticoagulant effect for up to 1 month ( 38 , 39 ), which significantly improves patient compliance by eliminating the need for routine monitoring and avoiding the effects of discontinuation or irregular readministration after discontinuation.…”

Effects of Itraconazole and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Milvexian, A Factor XIa Inhibitor

“…In preclinical models of arterial and venous thrombosis, milvexian demonstrated antithrombotic activity while preserving homeostasis [20,21]. In subsequent clinical studies, milvexian was generally safe and well tolerated in healthy participants and in those with hepatic and renal impairment [22][23][24].…”