Lilly-NUS Centre for Clinical Pharmacology, Singapore.
Br J Clin Pharmacol. 2012 Jan;73(1):93-105. doi: 10.1111/j.1365-2125.2011.04049.x.
This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel.
Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)].
Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001).
Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.
本开放标签、两周期、随机、交叉研究旨在确定 CYP2C19 功能降低变异对普拉格雷和氯吡格雷的活性代谢物暴露和血小板反应的影响。
90 名健康的中国受试者按 CYP2C19 表型分层，随机分配接受普拉格雷 10mg 或氯吡格雷 75mg 治疗 10 天，然后洗脱 14 天，再接受另一种药物治疗 10 天。83 名受试者完成了两个治疗期。在指定时间点采集血样，测量每种药物的活性代谢物（普拉格雷-AM 和氯吡格雷-AM）浓度，并通过透光比浊法测定血小板聚集抑制率（IPA）。CYP2C19 基因型分为三种预测表型组：快速代谢者[RMs（*1/*1）]、杂合子或中间代谢者[IMs（*1/*2，*1/*3）]和弱代谢者[PMs（*2/*2，*2/*3）]。
IMs 和 RMs 的普拉格雷-AM 暴露相似（90%置信区间为 0.85，1.03），PMs 略低于 IMs（90%置信区间为 0.74，0.99），而氯吡格雷-AM 暴露在 IMs 中明显低于 RMs（90%置信区间为 0.62，0.83），在 PMs 中明显低于 IMs（90%置信区间为 0.53，0.82）。在接受普拉格雷治疗的受试者中，IPA 在 RMs、IMs 和 PMs 之间更为一致（分别为 80.2%、84.2%和 80.2%），而在接受氯吡格雷治疗的受试者中，IPA 则更为不一致（分别为 59.7%、56.2%和 36.8%；P<0.001）。
与氯吡格雷相比，普拉格雷显示出更高的活性代谢物暴露和更一致的药效反应，这证实了先前研究的观察结果，即 CYP2C19 表型在氯吡格雷反应变异性中起重要作用，但对普拉格雷的反应没有影响。
