title: In vivo quantitative prediction of the effect of gene polymorphisms and drug interactions on drug exposure for CYP2C19 substrates.
abstract: We present a unified quantitative approach to predict the in vivo alteration in drug exposure caused by either cytochrome P450 (CYP) gene polymorphisms or CYP-mediated drug-drug interactions (DDI). An application to drugs metabolized by CYP2C19 is presented. The metrics used is the ratio of altered drug area under the curve (AUC) to the AUC in extensive metabolizers with no mutation or no interaction. Data from 42 pharmacokinetic studies performed in CYP2C19 genetic subgroups and 18 DDI studies were used to estimate model parameters and predicted AUC ratios by using Bayesian approach. Pharmacogenetic information was used to estimate a parameter of the model which was then used to predict DDI. The method adequately predicted the AUC ratios published in the literature, with mean errors of -0.15 and -0.62 and mean absolute errors of 0.62 and 1.05 for genotype and DDI data, respectively. The approach provides quantitative prediction of the effect of five genotype variants and 10 inhibitors on the exposure to 25 CYP2C19 substrates, including a number of unobserved cases. A quantitative approach for predicting the effect of gene polymorphisms and drug interactions on drug exposure has been successfully applied for CYP2C19 substrates. This study shows that pharmacogenetic information can be used to predict DDI. This may have important implications for the development of personalized medicine and drug development.
authors: Service Pharmaceutique, Groupement Hospitalier de Gériatrie, Hospices Civils de Lyon, Lyon, France. sylvain.goutelle@chu-lyon.fr
authors: Sylvain
authors: S
authors: Goutelle
authors: Laurent
authors: L
authors: Bourguignon
authors: Nathalie
authors: N
authors: Bleyzac
authors: Johanna
authors: J
authors: Berry
authors: Fannie
authors: F
authors: Clavel-Grabit
authors: Michel
authors: M
authors: Tod
mesh_terms: D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D001499:Bayes Theorem; D001682:Biological Availability; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D057285:Precision Medicine; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013379:Substrate Specificity
chemical_list: D004364:Pharmaceutical Preparations; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19