Kobayashi Masahiko, Kajiwara Miyuki, Hasegawa Setsuo
Therapeutic Strategy Unit Asia Pacific R&D, Sanofi K.K.
J Atheroscler Thromb. 2015;22(11):1186-96. doi: 10.5551/jat.28639. Epub 2015 Jun 9.
We investigated the safety of 600/150 mg regimen of clopidogrel and the pharmacodynamics and pharmacokinetics of both 300/75 mg regimen and 600/150 mg regimen of clopidogrel in 72 Japanese subjects.
A randomized study was conducted in healthy Japanese male subjects. Eligible subjects were stratified by dose regimen (300 mg loading dose of clopidogrel on day 1 followed by a 75 mg maintenance dose from days 2 to 7 or a 600 mg loading dose of clopidogrel on day 1 followed by a 150 mg maintenance dose from days 2 to 7) and CYP2C19 metabolizer group [extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs)]. Platelet aggregation and platelet reactivity were evaluated by measuring the maximum platelet aggregation intensity (MAI) induced by 5 and 20 μM ADP, phosphorylation of vasodilator-stimulated phosphoprotein (VASP), and P2Y12 reaction units (PRU) using the VerifyNow system, respectively. We also measured the plasma concentrations of clopidogrel and its active metabolite H4.
No treatment emergent adverse events in the 300/75 mg and 600/150 mg regimen were observed in EMs, IMs, and PMs. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP in the 300/75 mg and 600/150 mg clopidogrel regimens, and MAI (%) in IM group was equipotent to EM irrespective of the clopidogrel dosage. The double dose regimen decreased MAI in the PM group as equipotent to the IM group receiving the standard dose regimen without the extension of bleeding time. No clear relationship of exposure to clopidogrel and CYP2C19 function was observed, whereas active metabolite H4 exposure was likely to be related to CYP2C19 function.
Clopidogrel in the 600/150 mg regimen was well tolerated. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP and anti-platelet activities analyzed by VASP and VerifyNow test in the 300/75 mg and 600/150 mg regimens in healthy Japanese subjects.
我们在72名日本受试者中研究了氯吡格雷600/150mg方案的安全性以及氯吡格雷300/75mg方案和600/150mg方案的药效学和药代动力学。
在健康的日本男性受试者中进行了一项随机研究。符合条件的受试者按剂量方案（第1天给予氯吡格雷300mg负荷剂量，随后从第2天至第7天给予75mg维持剂量，或第1天给予氯吡格雷600mg负荷剂量，随后从第2天至第7天给予150mg维持剂量）和CYP2C19代谢酶组[广泛代谢者（EMs）、中间代谢者（IMs）和慢代谢者（PMs）]进行分层。分别通过测量5和20μM ADP诱导的最大血小板聚集强度（MAI）、血管舒张刺激磷蛋白（VASP）的磷酸化以及使用VerifyNow系统测定的P2Y12反应单位（PRU）来评估血小板聚集和血小板反应性。我们还测量了氯吡格雷及其活性代谢产物H4的血浆浓度。
在EMs、IMs和PMs中，未观察到300/75mg和600/150mg方案出现治疗突发不良事件。在氯吡格雷300/75mg和600/150mg方案中，所有CYP代谢酶组由ADP诱导的MAI（%）均较低，并且无论氯吡格雷剂量如何，IM组的MAI（%）与EM组相当。双倍剂量方案使PM组的MAI降低程度与接受标准剂量方案的IM组相当，且未延长出血时间。未观察到氯吡格雷暴露与CYP2C19功能之间存在明确关系，而活性代谢产物H4的暴露可能与CYP2C19功能有关。
氯吡格雷600/150mg方案耐受性良好。在健康日本受试者中，所有CYP代谢酶组在氯吡格雷300/75mg和600/150mg方案中由ADP诱导的MAI（%）均较低，并且通过VASP和VerifyNow试验分析的抗血小板活性也较低。
