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

AbstractClopidogrel 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 20th percentile of baseline PRU levels were shown to require 2.5 –3 times higher doses than those in the b...
Source: CPT: Pharmacometrics and Systems Pharmacology - Category: Drugs & Pharmacology Authors: Tags: ARTICLE Source Type: research