Physiologically-Based Pharmacokinetic-Pharmacodynamics Model Characterizing CYP2C19 Polymorphisms to Predict Clopidogrel Pharmacokinetics and Its Anti-Platelet Aggregation Effect Following Oral Administration to Coronary Artery Disease Patients With or Without Diabetes

Frontiers in Pharmacology

Ru-jun Xu¹  Li Liu¹  Wei-min Kong¹  Xiao-dong Liu¹  Xiao-fei An³  Jian-jun Zou⁴ 

[1] Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University, Nanjing, China;Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China;Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinse Medicine, Nanjing, China;School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China;

关键词: clopidogrel;    PBPK-PD model;    coronary artery disease;    diabetes mellitus;    CYP2C19 polymorphism;    carboxylesterase 1 activity;   

DOI  :  10.3389/fphar.2020.593982

来源: DOAJ

【 摘 要 】

Background and Objective: Clopidogrel (CLOP) is commonly used in coronary artery disease (CAD) patients with or without diabetes (DM), but these patients often suffer CLOP resistance, especially those with diabetes. This study was aimed to develop a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and pharmacodynamics of clopidogrel active metabolite (CLOP-AM) in CAD patients with or without DM.Methods: The PBPK-PD model was first established and validated in healthy subjects and then in CAD patients with or without DM. The influences of CYP2C19, CYP2C9, CYP3A4, carboxylesterase 1 (CES1), gastrointestinal transit rates (Kt,i) and platelets response to CLOP-AM (kirre) on predicted pharmacokinetics and pharmacodynamics were investigated, followed with their individual and integrated effects on CLOP-AM pharmacokinetics due to changes in DM status.Results: Most predictions fell within 0.5–2.0 folds of observations, indicating successful predictions. Sensitivity analysis showed that contributions of interested factors to pharmacodynamics were CES1> kirre> Kt,i> CYP2C19 > CYP3A4> CYP2C9. Mimicked analysis showed that the decreased exposure of CLOP-AM by DM was mainly attributed to increased CES1 activity, followed by decreased CYP2C19 activity.Conclusion: The pharmacokinetics and pharmacodynamics of CLOP-AM were successfully predicted using the developed PBPK-PD model. Clopidogrel resistance by DM was the integrated effects of altered Kt,i, CYP2C19, CYP3A4, CES1 and kirre.

【 授权许可】

Unknown