Population Pharmacokinetic-Pharmacodynamic Modeling of Clopidogrel for Dose Regimen Optimization based on CYP2C19 Phenotypes: A Proof of Concept Study.

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 (PM) 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 1 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 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 sub-model of clopidogrel H4 that stimulated the fractional turnover rate of PRU levels showed the best performance. Monte Carlo simulations suggested that PM require 3-4 times higher doses than extensive metabolizers to reach the target PRU level. Individuals within the top 20 th percentile of baseline PRU levels were shown to require 2.5-3 times higher doses than those in the bottom 20 th 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.