Population pharmacokinetic-pharmacodynamic modeling of clopidogrel for dose regimen optimization based on CYP2C19 phenotypes: A proof of concept study.

Autor: Jung YS; Department of Convergence Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea., Jin BH; Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Korea., Park MS; Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Korea.; Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea., Kim CO; Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, Seoul, Korea., Chae D; Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2024 Jan; Vol. 13 (1), pp. 29-40. Date of Electronic Publication: 2023 Oct 04.
DOI: 10.1002/psp4.13053
Abstrakt: Clopidogrel is an antiplatelet drug used to reduce the risk of acute coronary syndrome and stroke. It is converted by CYP2C19 to its active metabolite; therefore, poor metabolizers (PMs) of CYP2C19 exhibit diminished antiplatelet effects. Herein, we conducted a proof-of-concept study for using population pharmacokinetic-pharmacodynamic (PK-PD) modeling to recommend a personalized clopidogrel dosing regimen for individuals with varying CYP2C19 phenotypes and baseline P2Y12 reaction unit (PRU) levels. Data from a prospective phase I clinical trial involving 36 healthy male participants were used to develop the population PK-PD model predicting the concentrations of clopidogrel, clopidogrel H4, and clopidogrel carboxylic acid, and linking clopidogrel H4 concentrations to changes in PRU levels. A two-compartment model effectively described the PKs of both clopidogrel and clopidogrel carboxylic acid, and a one-compartment model of those of clopidogrel H4. The CYP2C19 phenotype was identified as a significant covariate influencing the metabolic conversion of the parent drug to its metabolites. A PD submodel of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PMs require three to four times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20th percentile of baseline PRU levels were shown to require 2.5-3 times higher doses than those in the bottom 20th percentile. We successfully developed a population PK-PD model for clopidogrel considering the impact of CYP2C19 phenotypes and baseline PRU levels. Further studies are necessary to confirm actual dosing recommendations for clopidogrel.
(© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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