Gurbel P A, Bergmeijer T O, Tantry U S, ten Berg J M, Angiolillo D J, James S, Lindahl T L, Svensson P, Jakubowski J A, Brown P B, Duvvuru S, Sundseth S, Walker J R, Small D, Moser B A, Winters K J, Erlinge D
Paul A. Gurbel, MD, Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, 2401 W. Belvedere Ave, Baltimore, MD 21215, USA, Tel.: +1 410 601 9600, Fax: +1 410 601 9601, E-mail:
Thromb Haemost. 2014 Sep 2;112(3):589-97. doi: 10.1160/TH13-10-0891. Epub 2014 Jul 10.
CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.
细胞色素P450 2C19（CYP2C19）基因型已被证明会影响对75毫克氯吡格雷的反应，但不会影响对10毫克普拉格雷的反应。在此，我们利用两项针对稳定型冠状动脉疾病（CAD）患者的药代动力学（PK）/药效学（PD）研究（GENERATIONS和FEATHER）的数据，评估了CYP2C19代谢状态对5毫克和10毫克普拉格雷以及75毫克氯吡格雷的PK和PD反应的影响。通过CYP2C19预测的表型（广泛代谢者[EM；N = 154]，*2-*8非携带者，与代谢降低者[RM；N = 41]，*2-*8携带者/*17非携带者）分析活性代谢物浓度（曲线下面积，AUC[0-tlast]）、通过光透射聚集法测量的最大血小板聚集（MPA）、血管舒张剂刺激的磷蛋白血小板反应性指数以及VerifyNow P2Y12血小板反应单位（VN-PRU）。对于5毫克和10毫克普拉格雷，AUC(0-tlast)不受代谢状态的影响（几何平均EM/RM比值分别为1.00，95%置信区间[CI]：0.86,1.17，p>0.99；以及0.97，95% CI：0.85,1.12，p = 0.71），但在接受75毫克氯吡格雷的RM中较低（1.37，95% CI：1.14,1.65，p<0.001）。对于5毫克普拉格雷，血小板反应性不受CYP2C19代谢状态的显著影响，对于10毫克普拉格雷，通过MPA和VN-PRU测量也不受影响，但对于75毫克氯吡格雷，代谢降低者的血小板反应性显著更高（所有测量p<0.01）。10毫克普拉格雷显示出比75毫克氯吡格雷更强的抗血小板作用（所有比较p<0.001）。5毫克普拉格雷在RM中显示出比75毫克氯吡格雷更强的抗血小板作用（所有p<0.001），在EM中作用相当（所有p≥0.37）。与氯吡格雷不同，普拉格雷活性代谢物的PK不受CYP2C19基因型的影响。无论代谢状态如何，10毫克普拉格雷的抗血小板作用更强，与75毫克氯吡格雷相比，5毫克普拉格雷在RM中作用更强，在EM中作用相当。
