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.

中文翻译：

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与健康受试者相比，轻度或中度肝受损受试者中 Milvexian 的单剂量药代动力学

背景

肝功能不全的患者接受主要通过肝脏代谢的抗血栓药物可能存在出血风险。Milvexian (BMS-986177/JNJ-70033093) 是一种小分子活性位点活化因子 XI (FXIa) 抑制剂。FXI 的调节可以提供全身抗凝作用，而不会增加临床上严重出血的风险。

客观的

这项开放标签研究评估了轻度或中度肝损伤对 Milvexian 药代动力学的影响，以评估其对安全性和剂量的影响。

方法

轻度肝功能不全 ( n = 9)、中度肝功能不全 ( n = 8) 和肝功能正常 ( n = 9)的参与者接受单剂量 Milvexian 60 mg 。将健康参与者与肝损伤参与者按体重、年龄和性别进行匹配。对自然对数变换的 Milvexian 暴露参数进行方差分析，以肝功能组作为固定效应。

结果

单剂量 Milvexian 60 mg 通常耐受性良好，没有严重不良事件 (AE)、出血 AE 或因 AE 导致的停药。总米尔维克斯观察到的最大血浆浓度和从零时间外推到无限时间的血浆浓度-时间曲线下面积的几何平均比（90%置信区间）分别为1.180（0.735-1.895）和1.168（0.725-1.882）。轻度肝损伤与正常肝功能相比，中度肝损伤与正常肝功能分别为 1.140 (0.699-1.857) 和 0.996 (0.609-1.628)。在各组中，观察到与米尔维鲜暴露相关的活化部分凝血活酶时间增加。

结论

肝功能正常、轻度受损和中度受损的参与者对米尔维显的耐受性良好。观察到的药代动力学变化表明，轻度或中度肝功能不全的患者不太可能需要调整剂量。临床试验注册Clinicaltrials.gov 标识符：NCT02982707。