Small David S, Farid Nagy A, Li Ying G, Ernest C Steven, Payne Christopher D, Salazar Daniel E, Winters Kenneth J
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Curr Med Res Opin. 2008 Aug;24(8):2251-7. doi: 10.1185/03007990802205985.
Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrel's solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption. This study evaluated the influence of ranitidine coadministration on the pharmacokinetics and pharmacodynamics of the respective active metabolite of prasugrel and clopidogrel.
In this open-label, two-period, two-treatment, crossover study, 47 healthy male subjects were randomized to one of two study arms, receiving either prasugrel (60-mg loading dose [LD], 10-mg maintenance dose [MD] for 7 days; n = 23) or clopidogrel (600-mg LD, 75-mg MD for 7 days; n = 24). In one treatment period, subjects received prasugrel or clopidogrel alone, and in the alternate period received the same thienopyridine with ranitidine (150 mg twice daily, starting 1 day before the LD). Pharmacokinetic parameter estimates (AUC(0-t last), C(max), and t(max)) and inhibition of platelet aggregation (IPA) by light transmission aggregometry were assessed at multiple time points after the LD and final MD.
Ranitidine had no clinically significant effect on the area under the plasma-concentration-time curve (AUC) and did not affect the time to C(max) (t(max)) for active metabolites of either prasugrel or clopidogrel. It reduced the geometric mean maximum concentrations of active metabolite (C(max)) after a prasugrel and clopidogrel LD by 14% and 10%, respectively, but these differences were not statistically significant. When coadministered with a 60-mg prasugrel LD, ranitidine did not affect the time to, or magnitude of, peak IPA, but did result in a modest reduction at 0.5 h from 67.4 to 55.1% (p < 0.001). Ranitidine did not affect prasugrel IPA during MD. For clopidogrel, IPA was not affected by ranitidine. Prasugrel and clopidogrel were both well-tolerated, with/without ranitidine.
Results from this study suggest that there is no significant drug-drug interaction between oral ranitidine therapy and concomitantly-administered prasugrel or clopidogrel.
氯吡格雷是一种口服噻吩并吡啶类抗血小板药物，用于治疗急性冠状动脉综合征（ACS）患者的动脉粥样硬化血栓形成事件。普拉格雷是一种新型口服噻吩并吡啶类药物，正在进行研究，用于降低接受经皮冠状动脉介入治疗的ACS患者的动脉粥样硬化血栓形成事件。普拉格雷的溶解度随pH值升高而降低，这表明同时服用可提高胃内pH值的药物可能会降低普拉格雷的吸收速率和/或程度。本研究评估了雷尼替丁联合用药对普拉格雷和氯吡格雷各自活性代谢产物的药代动力学和药效学的影响。
在这项开放标签、两阶段、双治疗、交叉研究中，47名健康男性受试者被随机分为两个研究组之一，分别接受普拉格雷（60mg负荷剂量[LD]，10mg维持剂量[MD]，共7天；n = 23）或氯吡格雷（600mg LD，75mg MD，共7天；n = 24）。在一个治疗阶段，受试者单独接受普拉格雷或氯吡格雷，在另一个阶段接受相同的噻吩并吡啶类药物与雷尼替丁（每日两次，每次150mg，从LD前1天开始）。在LD和最后一次MD后的多个时间点评估药代动力学参数估计值（AUC(0 - t last)、C(max)和t(max)）以及通过光透射聚集法测定的血小板聚集抑制率（IPA）。
雷尼替丁对普拉格雷或氯吡格雷活性代谢产物的血浆浓度 - 时间曲线下面积（AUC）无临床显著影响，也不影响达到C(max)的时间（t(max)）。它使普拉格雷和氯吡格雷LD后活性代谢产物的几何平均最大浓度（C(max)）分别降低了14%和10%，但这些差异无统计学意义。与60mg普拉格雷LD联合使用时，雷尼替丁不影响达到峰值IPA的时间或幅度，但确实导致0.5小时时的IPA从67.4%适度降低至55.1%（p < 0.001）。雷尼替丁在MD期间不影响普拉格雷的IPA。对于氯吡格雷，IPA不受雷尼替丁影响。普拉格雷和氯吡格雷在有/无雷尼替丁的情况下耐受性均良好。
本研究结果表明，口服雷尼替丁治疗与同时服用的普拉格雷或氯吡格雷之间不存在显著的药物相互作用。
