Frost Charles, Nepal Sunil, Wang Jessie, Schuster Alan, Byon Wonkyung, Boyd Rebecca A, Yu Zhigang, Shenker Andrew, Barrett Yu Chen, Mosqueda-Garcia Rogelio, Lacreta Frank
Bristol-Myers Squibb, Princeton, NJ, USA.
Br J Clin Pharmacol. 2013 Nov;76(5):776-86. doi: 10.1111/bcp.12106.
Apixaban 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.
This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg 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).
Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ~3 h 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.
Multiple 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.
阿哌沙班是一种口服Xa因子抑制剂，已被批准用于预防心房颤动患者的中风以及接受择期髋关节或膝关节置换手术患者的血栓预防，目前正在进行治疗静脉血栓栓塞的研究。本研究考察了多次给药阿哌沙班的安全性、药代动力学和药效学。
本双盲、随机、安慰剂对照、平行组、多次给药剂量递增研究分六个连续剂量组进行，即阿哌沙班每日两次2.5、5、10和25mg以及每日一次10和25mg，每组8名健康受试者。在每个剂量组内，受试者按3:1随机分为口服阿哌沙班或安慰剂组，给药7天。对受试者进行安全性评估并监测不良事件（AE）。采集血样以测定阿哌沙班血浆浓度、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）。
48名受试者被随机分组并接受治疗（阿哌沙班组，n = 36；安慰剂组，n = 12）；一名每日两次接受2.5mg治疗的受试者因不良事件（头痛和恶心）停药。未观察到剂量限制性不良事件。阿哌沙班在给药后约3小时达到最大血浆浓度。暴露量大致随剂量成比例增加。阿哌沙班在第3天达到稳态浓度，蓄积指数为1.3 - 1.9。每日两次给药方案的峰谷比低于每日一次给药方案。凝血时间显示出与剂量相关的增加，与血浆浓度 - 时间曲线相符。
在10倍剂量范围内，多次口服阿哌沙班安全且耐受性良好，药代动力学变异性低，凝血时间测量值与浓度相关增加。
