Physiologically Based Pharmacokinetic Modeling for Sequential Metabolism: Effect of CYP2C19 Genetic Polymorphism on Clopidogrel and Clopidogrel Active Metabolite Pharmacokinetics
| Autor: | Xavier Boulenc, Fabrice Hurbin, Nassim Djebli, Gérard Fabre, Eric Sultan, David Fabre |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Physiologically based pharmacokinetic modelling Ticlopidine Adolescent Metabolite Amiodarone Secondary Metabolism Pharmaceutical Science CYP2C19 Pharmacology Models Biological Polymorphism Single Nucleotide Loading dose Intestinal absorption Young Adult chemistry.chemical_compound Double-Blind Method Pharmacokinetics Humans Drug Interactions Tissue Distribution Dronedarone Biotransformation Active metabolite Aged Cross-Over Studies Maintenance dose Reproducibility of Results Middle Aged Clopidogrel Cytochrome P-450 CYP2C19 Intestinal Absorption chemistry Area Under Curve Cytochrome P-450 CYP2C19 Inhibitors |
| Zdroj: | Drug Metabolism and Disposition. 43:510-522 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.114.062596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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