Drug design, development and therapy · 2025
Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Milvexian in Healthy Chinese Adults.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Luo Zhu, Wang Jie, Niu Zhuolu, Hu Cuili, Chintala Madhu, Luo Xinchao, Lee Tsung-I, Plotnikov Alexei N, Zannikos Peter
Аннотация
BACKGROUND: 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.
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.