title: Physiologically based pharmacokinetic modeling for sequential metabolism: effect of CYP2C19 genetic polymorphism on clopidogrel and clopidogrel active metabolite pharmacokinetics.
abstract: 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.
authors.affiliation: Sanofi R&D, Drug Disposition, Disposition Safety and Animal Research, Montpellier, France nassim.djebli@sanofi.com.
authors.forename: Nassim
authors.initials: N
authors.lastname: Djebli
authors.affiliation: Sanofi R&D, Drug Disposition, Disposition Safety and Animal Research, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Fabre
authors.affiliation: Sanofi R&D, Drug Disposition, Disposition Safety and Animal Research, Montpellier, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Boulenc
authors.affiliation: Sanofi R&D, Drug Disposition, Disposition Safety and Animal Research, Montpellier, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Fabre
authors.affiliation: Sanofi R&D, Drug Disposition, Disposition Safety and Animal Research, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Sultan
authors.affiliation: Sanofi R&D, Drug Disposition, Disposition Safety and Animal Research, Montpellier, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Hurbin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000638:Amiodarone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019540:Area Under Curve; D001711:Biotransformation; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D065689:Cytochrome P-450 CYP2C19 Inhibitors / Q000494:pharmacology; D004311:Double-Blind Method; D000077764:Dronedarone; D004347:Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D064210:Secondary Metabolism / Q000502:physiology*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D065689:Cytochrome P-450 CYP2C19 Inhibitors; C540904:2-oxo-clopidogrel; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000077764:Dronedarone; D000638:Amiodarone; D013988:Ticlopidine