Physiologically Based Pharmacokinetic Modeling for Sequential Metabolism: Effect of CYP2C19 Genetic Polymorphism on Clopidogrel and Clopidogrel Active Metabolite Pharmacokinetics
Physiologically Based Pharmacokinetic Modeling for Sequential Metabolism: Effect of CYP2C19 Genetic Polymorphism on Clopidogrel and Clopidogrel Active Metabolite Pharmacokinetics
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DOI：
10.1124/dmd.114.062596
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发表时间：
2015-04-01
影响因子：
3.9
通讯作者：
Hurbin, Fabrice
中科院分区：
文献类型：
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作者：
Djebli, Nassim;Fabre, David;Hurbin, Fabrice
氯吡格雷是一种前药，需要在两个连续的细胞色素P450（P450）依赖性步骤中转化为其活性代谢产物（氯吡格雷-H4）。在本研究中，在Simcyp中使用特定的顺序代谢物模块，在4个具有不同表型CYP 2C 19活性的人群（弱、中等、快速和超快代谢者）中开发了氯吡格雷和氯吡-H4的动态生理药代动力学（PBPK）模型，接受300 mg负荷剂量，随后接受75 mg维持剂量。该模型使用几种方法进行了验证。首先，使用视觉预测检查方法比较在4个平衡CYP 2C 19表型代谢者组中进行的随机交叉研究中获得的预测-观察曲线下面积（AUC）（0-24）。其次，比较了每个表型组的预测试验和观察试验之间的个体间和试验间变异性（基于AUC（0-24）比较）。最后，使用先前开发和验证的基于生理学的PBPK决奈达隆模型，通过比较与或不与决奈达隆（中效CYP 3A 4抑制剂）联合给药的氯吡格雷和氯吡-H4的观察值，在药物-药物相互作用预测的基础上进行了进一步验证。无论治疗阶段如何（300 mg负荷剂量和75 mg末次维持剂量），在每个CYP 2C 19表型组中，PBPK模型均得到了氯吡格雷及其活性代谢产物氯吡-H4的充分验证。这是第一项提出全动态PBPK模型的研究，能够准确同时预测母体药物及其初级和次级代谢产物在代谢酶活性遗传上不同的人群中的药代动力学。
Clopidogrel is a prodrug that needs to be converted to its active metabolite (clopi-H4) in two sequential cytochrome P450 (P450)-dependent steps. In the present study, a dynamic physiologically based pharmacokinetic (PBPK) model was developed in Simcyp for clopidogrel and clopi-H4 using a specific sequential metabolite module in four populations with phenotypically different CYP2C19 activity (poor, intermediate, extensive, and ultrarapid metabolizers) receiving a loading dose of 300 mg followed by a maintenance dose of 75 mg. This model was validated using several approaches. First, a comparison of predicted-to-observed area under the curve (AUC) (0-24) obtained from a randomized crossover study conducted in four balanced CYP2C19-phenotype metabolizer groups was performed using a visual predictive check method. Second, the interindividual and intertrial variability (on the basis of AUC(0-24) comparisons) between the predicted trials and the observed trial of individuals, for each phenotypic group, were compared. Finally, a further validation, on the basis of drug-drug-interaction prediction, was performed by comparing observed values of clopidogrel and clopi-H4 with or without dronedarone (moderate CYP3A4 inhibitor) coadministration using a previously developed and validated physiologically based PBPK dronedarone model. The PBPK model was well validated for both clopidogrel and its active metabolite clopi-H4, in each CYP2C19-phenotypic group, whatever the treatment period (300-mg loading dose and 75-mg last maintenance dose). This is the first study proposing a full dynamic PBPK model able to accurately predict simultaneously the pharmacokinetics of the parent drug and of its primary and secondary metabolites in populations with genetically different activity for a metabolizing enzyme.