Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline R&D, Ermington, Australia.
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline R&D, Stevenage, UK.
Pharmacol Res Perspect. 2022 Apr;10(2):e00946. doi: 10.1002/prp2.946.
Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population-specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady-state AUC of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26-9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4-30.1] ng·h/ml, p < .001) population. In addition to CYP2C19-poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity.
氯吡格雷的治疗反应与 CYP2C19 活性相关，这是通过形成活性 H4 代谢物实现的。本研究旨在建立一个欧洲人群的氯吡格雷及其代谢物的基于生理学的药代动力学（PBPK）模型，通过 CYP2C19 表型预测日本人群的药代动力学，并探讨临床和人口统计学因素的影响。
使用来自已发表研究的血浆数据，我们开发并验证了一个 PBPK 模型，用于描述氯吡格雷的两种代谢途径（H4 代谢物，酰基葡萄糖醛酸代谢物）的欧洲人群。随后，评估了该模型在日本人群中的预测。接着，研究了 CYP2C19 活性、氟伏沙明合用（CYP2C19 抑制剂）以及人群特异性因素（年龄、性别、BMI、体重、癌症、肝和肾功能障碍）对氯吡格雷及其代谢物药代动力学的影响。
氯吡格雷和代谢物暴露参数的预测/观察比值是可以接受的（两倍接受标准）。对于所有 CYP2C19 表型，H4 代谢物的稳态 AUC 在日本人群中均低于欧洲人群（例如，EM，7.69 [6.26-9.45] ng·h/ml；几何均数[95%CI]；EM，24.8 [20.4-30.1] ng·h/ml，p <.001）。除了 CYP2C19 弱代谢表型外，氟伏沙明合用、肝和肾功能障碍均会降低 H4 代谢物但不降低酰基葡萄糖醛酸代谢物浓度。这是第一个描述氯吡格雷两种主要代谢途径的 PBPK 模型，可通过 CYP2C19 表型应用于欧洲和日本人群。这两个人群之间的差异似乎主要由 CYP2C19 肝活性的变化决定。
