Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects
Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects
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DOI：
10.1111/bcp.12106
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发表时间：
2013-11-01
影响因子：
3.4
通讯作者：
LaCreta, Frank
中科院分区：
文献类型：
--
作者：
Frost, Charles;Nepal, Sunil;LaCreta, Frank
AimApixaban是一种口服Xa因子抑制剂，被批准用于选择性髋关节或膝关节置换术患者房颤和血栓预防的卒中预防，并正在开发用于静脉血栓栓塞的治疗。本研究考察了多剂量阿哌沙班的安全性、药代动力学和药效学。方法采用双盲、随机、安慰剂对照、平行组、多重剂量递增研究，分为阿哌沙班2.5、5、10和25mg每日2次、10和25mg每日1次6个顺序剂量组，每个组8名健康受试者。在每个小组中，受试者被随机分配（3:1）口服阿哌沙班或安慰剂7天。受试者接受安全性评估并监测不良事件（ae）。取血检测阿哌沙班血药浓度、国际标准化比值（INR）、活化部分凝血活酶时间（aPTT）和改良凝血酶原时间（mPT）。结果48例受试者随机接受治疗（阿哌沙班36例，安慰剂12例）；1名受试者每日2次，每次2.5mg，因ae（头痛和恶心）停用。未观察到剂量限制性ae。阿哌沙班最大血药浓度在给药后约3h达到。暴露量的增加大约与剂量成正比。阿哌沙班在第3天达到稳态浓度，积累指数为1.3 ~ 1.9。每日两次与每日一次的峰谷比较低。凝血时间随血浆浓度-时间曲线呈剂量相关增加。结论多剂量口服阿哌沙班是安全的，在10倍剂量范围内具有良好的耐受性，药代动力学具有低变异性，凝血时间测量呈浓度相关增加。
AimApixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban.MethodThis double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25mg twice daily and 10 and 25mg once daily- with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT).ResultsForty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved approximate to 3h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3-1.9. Peak:trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration-time profile.ConclusionMultiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.