Influence of genetic co-factors on the population pharmacokinetic model for clopidogrel and its active thiol metabolite

Abstract

Purpose

A high interindividual variability is observed in the pharmacokinetics of clopidogrel, a widely used antiplatelet drug. In the present study, a joint parent-metabolite population pharmacokinetic model was developed to adequately describe observed concentrations of clopidogrel and its active thiol metabolite (H4).

Methods

The study included 63 patients undergoing elective coronarography or percutaneous coronary intervention. The population pharmacokinetic model was developed in the NONMEM 7.3 software, and first-order conditional estimation method with interaction was applied. Also, the influence of covariates was evaluated (age, weight, body mass index (BMI), obesity defined as BMI ≥ 30 kg/m², sex, diabetes mellitus, co-administration of PPI or statins, presence of CYP2C19*2, CYP2C19*17, CYP3A4*1G alleles, and ABCB1 3435 TT genotype).

Results

It was found that the only significant covariate was the presence of CYP2C19*2 allele, which had an impact on lower conversion of clopidogrel to H4. As a result, predicted area under the time-concentration curve values was lower in carriers of this allele, with median 5.94 ng h/ml (interquartile range 3.92–12.51 [ng∙h/ml]) vs. 12.70 ng h/ml in non-carriers (interquartile range, 7.00–19.39 [ng∙h/ml]), respectively (p = 0.004).

Conclusions

Developed model predicts that the only significant covariate influencing the observed concentrations and therefore the exposure to the active H4 metabolite is the presence of CYP2C19*2 allele.

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