Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Milvexian in Healthy Chinese Adults

Zhu Luo,1 Jie Wang,2 Zhuolu Niu,3 Cuili Hu,4 Madhu Chintala,5 Xinchao Luo,3 Tsung-I Lee,3 Alexei N Plotnikov,5 Peter Zannikos5 1Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Hematology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Johnson & Johnson, Shanghai, People’s Republic of China; 4Johnson & Johnson, Beijing, People’s Republic of China; 5Johnson & Johnson, Raritan, NJ, USACorrespondence: Zhuolu Niu, Janssen Research & Development, 65 Gui Qing Road, Shanghai, 200233, People’s Republic of China, Email [email protected]: Milvexian is a small molecule, selective factor XIa (FXIa) inhibitor being developed as an oral anticoagulant. This study assessed the pharmacokinetics, pharmacodynamics (activated partial thromboplastin time [aPTT]), and safety of milvexian in healthy Chinese subjects.Methods: Part 1: Thirty subjects were randomly assigned 1:1:1 to receive milvexian 25 mg on Day 1 followed by 25 mg once daily (QD) on Days 5– 12; milvexian 25 mg twice daily at 12-hour intervals (BID) on Days 1– 8; or milvexian 100 mg BID on Days 1– 8. Part 2: Ten subjects received milvexian 200 mg on Day 1 followed by 200 mg BID on Days 5– 12. Plasma samples were collected for pharmacokinetics and aPTT assessments. Safety and tolerability were assessed.Results: Milvexian was rapidly absorbed (median tmax of 3– 4 hours after a single dose and repeated administration). Mean maximum concentrations or area under the concentration-time curve values of milvexian in plasma after single doses or BID administration of 25 mg, 100 mg, or 200 mg increased in a dose-dependent manner. Steady state conditions were achieved within 6 days of repeated administration based on milvexian trough concentration values. Mean terminal half-life values (9– 10 hours) were independent of the dose. Milvexian reversibly prolonged aPTT in a manner that was directly related to milvexian dose and exposure. All milvexian regimens were safe and well tolerated, with only mild treatment-emergent adverse events and no clinically significant bleeding events. No new safety signals were identified.Conclusion: The pharmacokinetic, pharmacodynamic, and safety profiles of milvexian demonstrate suitability for further clinical development in Chinese participants.Keywords: anticoagulant, aPTT, FXIa inhibitor, milvexian, pharmacokinetics