RT Journal Article
SR Electronic
T1 Physiologically Based Pharmacokinetic Modeling for Sequential Metabolism: Effect of CYP2C19 Genetic Polymorphism on Clopidogrel and Clopidogrel Active Metabolite Pharmacokinetics
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 510
OP 522
DO 10.1124/dmd.114.062596
VO 43
IS 4
A1 Nassim Djebli
A1 David Fabre
A1 Xavier Boulenc
A1 Gérard Fabre
A1 Eric Sultan
A1 Fabrice Hurbin
YR 2015
UL http://dmd.aspetjournals.org/content/43/4/510.abstract
AB Clopidogrel is a prodrug that needs to be converted to its active metabolite (clopi-H4) in two sequential cytochrome P450 (P450)-dependent steps. In the present study, a dynamic physiologically based pharmacokinetic (PBPK) model was developed in Simcyp for clopidogrel and clopi-H4 using a specific sequential metabolite module in four populations with phenotypically different CYP2C19 activity (poor, intermediate, extensive, and ultrarapid metabolizers) receiving a loading dose of 300 mg followed by a maintenance dose of 75 mg. This model was validated using several approaches. First, a comparison of predicted-to-observed area under the curve (AUC)0–24 obtained from a randomized crossover study conducted in four balanced CYP2C19-phenotype metabolizer groups was performed using a visual predictive check method. Second, the interindividual and intertrial variability (on the basis of AUC0–24 comparisons) between the predicted trials and the observed trial of individuals, for each phenotypic group, were compared. Finally, a further validation, on the basis of drug-drug–interaction prediction, was performed by comparing observed values of clopidogrel and clopi-H4 with or without dronedarone (moderate CYP3A4 inhibitor) coadministration using a previously developed and validated physiologically based PBPK dronedarone model. The PBPK model was well validated for both clopidogrel and its active metabolite clopi-H4, in each CYP2C19-phenotypic group, whatever the treatment period (300-mg loading dose and 75-mg last maintenance dose). This is the first study proposing a full dynamic PBPK model able to accurately predict simultaneously the pharmacokinetics of the parent drug and of its primary and secondary metabolites in populations with genetically different activity for a metabolizing enzyme.