Wagner Henrik, Angiolillo Dominick J, Ten Berg Jurrien M, Bergmeijer Thomas O, Jakubowski Joseph A, Small David S, Moser Brian A, Zhou Chunmei, Brown Patricia, James Stefan, Winters Kenneth J, Erlinge David
Department of Cardiology, Skane University Hospital, Lund University, Getingevägen 4, 221 85, Lund, Sweden,
J Thromb Thrombolysis. 2014;38(2):127-36. doi: 10.1007/s11239-013-0987-8.
Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, ≥60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 ± 3.7 kg) and HBW (n = 38, 84.7 ± 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC(0-tlast), was calculated by noncompartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 μM adenosine diphosphate (ADP), and residual platelet aggregation to 5 μM ADP), VerifyNow(®) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC(0-tlast) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p ≤ 0.01), PRU (207 ± 68 vs. 152 ± 57, p < 0.001), and VASP-PRI (56 ± 18 vs. 39 ± 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9%) and VASP-PRI (65 vs. 27%). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC(0-tlast) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.
体重是氯吡格雷反应的一个预测指标。然而，尚无前瞻性研究基于体重比较药效学（PD）和药代动力学（PK）数据。我们比较了体重较低（LBW，<60 kg）和体重较高（HBW，≥60 kg）的稳定型冠状动脉疾病患者服用75 mg氯吡格雷后的PD和PK效应。LBW组（n = 34，体重56.4 ± 3.7 kg）和HBW组（n = 38，体重84.7 ± 14.9 kg）接受阿司匹林治疗的患者服用75 mg氯吡格雷10 - 14天。通过给药后4小时内最后一个可量化浓度计算活性代谢物（氯吡格雷活性代谢物，Clop-AM）的浓度-时间曲线下面积（AUC(0-tlast)），采用非房室模型方法计算。进行光透射聚集法（LTA）（最大血小板聚集率以及对20 μM二磷酸腺苷（ADP）的血小板聚集抑制率，和对5 μM ADP的残余血小板聚集率）、VerifyNow(®) P2Y12反应单位（PRU）以及血管舒张剂相关刺激磷蛋白磷酸化血小板反应性指数（VASP-PRI）检测。HBW患者的平均AUC(0-tlast)低于LBW患者：分别为12.8 ng·h/mL和17.9 ng·h/mL。通过LTA（所有p≤0.01）、PRU（207 ± 68 vs. 152 ± 57，p < 0.001）和VASP-PRI（56 ± 18 vs. 39 ± 17，p < 0.001）检测发现，HBW患者的血小板反应性更高。采用PRU（35% vs. 9%）和VASP-PRI（65% vs. 27%）检测发现，更多HBW患者表现为治疗期高血小板反应性（HPR）。体重与PRU和VASP-PRI相关（均p < 0.001），与对数转换后的AUC(0-tlast)呈负相关（p < 0.001）。总之，与LBW患者相比，HBW患者的Clop-AM水平较低，血小板反应性和HPR发生率较高，这导致他们对氯吡格雷的反应欠佳。
