The AAPS Journal

, Volume 15, Issue 2, pp 415–426 | Cite as

In Vivo Quantitative Prediction of the Effect of Gene Polymorphisms and Drug Interactions on Drug Exposure for CYP2C19 Substrates

  • Sylvain Goutelle
  • Laurent Bourguignon
  • Nathalie Bleyzac
  • Johanna Berry
  • Fannie Clavel-Grabit
  • Michel Tod
  • Genophar II Working Group
Research Article


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.


CYP2C19 drug interactions personalized medicine pharmacogenetics quantitative prediction 

Supplementary material

12248_2012_9431_MOESM1_ESM.doc (40 kb)
ESM 1(DOC 39 kb)
12248_2012_9431_MOESM2_ESM.doc (3.5 mb)
ESM 2(DOC 3563 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Sylvain Goutelle
    • 1
    • 2
    • 3
    • 6
  • Laurent Bourguignon
    • 1
    • 3
  • Nathalie Bleyzac
    • 3
    • 4
  • Johanna Berry
    • 5
  • Fannie Clavel-Grabit
    • 5
  • Michel Tod
    • 2
    • 5
  • Genophar II Working Group
  1. 1.Service Pharmaceutique, Groupement Hospitalier de GériatrieHospices Civils de LyonLyonFrance
  2. 2.ISPB—Faculté de Pharmacie de LyonUniversité Lyon 1, Université de LyonLyonFrance
  3. 3.Laboratoire de Biométrie et Biologie Evolutive, UMR CNRS 5558Université Lyon 1VilleurbanneFrance
  4. 4.Institut d’Hématologie et d’Oncologie PédiatriqueLyonFrance
  5. 5.Service PharmaceutiqueHôpital de la Croix-Rousse, Hospices Civils de LyonLyonFrance
  6. 6.PharmacieHôpital Pierre GarraudLyonFrance

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