Xu_2020_Front.Pharmacol_11_593982

Reference

Title : 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 - Xu_2020_Front.Pharmacol_11_593982
Author(s) : Xu RJ , Kong WM , An XF , Zou JJ , Liu L , Liu XD
Ref : Front Pharmacol , 11 :593982 , 2020
Abstract :

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 (K (t,i)) and platelets response to CLOP-AM (k (irre)) 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> k (irre)> K (t,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 K (t,i), CYP2C19, CYP3A4, CES1 and k (irre).

PubMedSearch : Xu_2020_Front.Pharmacol_11_593982
PubMedID: 33519456

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Citations formats

Xu RJ, Kong WM, An XF, Zou JJ, Liu L, Liu XD (2020)
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
Front Pharmacol 11 :593982

Xu RJ, Kong WM, An XF, Zou JJ, Liu L, Liu XD (2020)
Front Pharmacol 11 :593982