Effect of Atorvastatin on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Subjects
Effect of Atorvastatin on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Subjects
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DOI：
10.1592/phco.28.12.1483
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发表时间：
2008-12-01
期刊：
影响因子：
4.1
通讯作者：
Winters, Kenneth J.
中科院分区：
文献类型：
--
作者：
Farid, Nagy A.;Small, David S.;Winters, Kenneth J.
研究目的。研究阿托伐他汀80 mg/d对噻吩并吡啶类药物普拉格雷和氯吡格雷的药代动力学和药效学的潜在影响。开放标签，随机、交叉、双臂、平行组研究。英国唯一的临床研究中心。69名18-60岁的健康男性。受试者接受负荷剂量的普拉格雷60 mg，随后接受维持剂量10 mg/天，或负荷剂量的氯吡格雷300 mg，随后接受75 mg/天。药物作为单药治疗给药1.0天，在阿托伐他汀80 mg/天的6天导入期后，相同剂量的阿托伐他汀与相应的噻吩并吡啶继续给药10天。治疗方案之间有14天的洗脱期。测量和主要结果。在第1天和第11天给药前和给药后的不同时间点采集血样，用于测定代谢物的血浆浓度，并测量由腺苷5 '-二磷酸20 μ M和血管舒张剂刺激的磷蛋白（WASP）诱导的血小板聚集。联合阿托伐他汀给药不会改变负荷剂量后普拉格雷或氯吡格雷活性代谢产物的暴露量，因此不会改变血小板聚集（IPA）的抑制作用。在维持给药期间，阿托伐他汀给药导致普拉格雷和氯吡格雷活性代谢物的血浆浓度-时间曲线下面积（AUC）值分别增加17%和28%。AUC的这些微小变化并未导致IPA对普拉格雷的反应发生显著变化，但确实导致氯吡格雷维持给药期间第11天部分（但非全部）时间点的IPA显著增加。负荷剂量后，阿托伐他汀与普拉格雷或氯吡格雷联合给药对VASP磷酸化没有影响。阿托伐他汀80 mg/天与普拉格雷或氯吡格雷联合给药，在负荷剂量后或维持剂量期间对任一药物的抗血小板反应均无负面影响。在负荷剂量或维持剂量后，高剂量阿托伐他汀对普拉格雷的药效学反应没有临床意义的影响，这表明合并使用这些药物的患者无需调整剂量。
Study Objective. To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.Design. Open-label., randomized, crossover, two-arm, parallel-group studySetting. Single clinical research center in the United Kingdom.Participants. Sixty-nine healthy men aged 18-60 years.Intervention. Subjects received either a loading dose of prasugrel 60 mg followed by a maintenance dose of 10 mg/day or a loading dose of clopidogrel 300 mg followed by 75 mg/day The drug was given as monotherapy for 1.0 days, and after a 6-day run-in period with atorvastatin 80 mg/day, the same dosage of atorvastatin was continued with the respective thienopyridine for 10 days. A 14-day washout period separated the treatment regimens.Measurements and Main Results. Blood samples were collected before and at various time points after dosing on days 1 and 11 for determination of plasma concentrations of metabolites and for measurement of platelet aggregation induced by adenosine 5'-diphosphate 20 mu M and vasodilator-stimulated phosphoprotein (WASP). Coadministration of atorvastatin did not alter exposure to active metabolites of prasugrel or clopidogrel after the loading dose and thus did not alter inhibition of platelet aggregation (IPA). During maintenance dosing, atorvastatin administration resulted in 17% and 28% increases in the area under the plasma concentration-time curve (AUC) values of prasugrel's and clopidogrel's active metabolites, respectively. These small changes in AUC did not result in a significant change in IPA response to prasugrel but did result in a significant increase in IPA during clopidogrel maintenance dosing at some, but not all, of the time points on day 11. Coadministration of atorvastatin with either prasugrel or clopidogrel had no effect on VASP phosphorylation relative to the thienopyridine alone after the loading dose.Conclusion. Coadministration of atorvastatin 80 mg/day with prasugrel or clopidogrel did not negatively affect the antiplatelet response to either drug after a loading dose or during maintenance dosing. The lack of a clinically meaningful effect of high-dose atorvastatin on the pharmacodynamic response to prasugrel after the loading or maintenance dose indicates that no dosage adjustment should be necessary in patients receiving these drugs concomitantly.