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The AAPS Journal

, Volume 19, Issue 2, pp 497–509 | Cite as

A Model for Predicting the Interindividual Variability of Drug-Drug Interactions

Research Article

Abstract

Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96–1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc = 1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.

KEY WORDS

cytochromes drug interactions interindividual variability pharmacokinetics prediction model 

Notes

Acknowledgments

This study was not supported by any academic, company, or sponsor fund.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • M. Tod
    • 1
    • 2
    • 3
  • L. Bourguignon
    • 1
    • 3
    • 4
  • N. Bleyzac
    • 2
    • 5
  • S. Goutelle
    • 1
    • 3
    • 4
  1. 1.Pharmacie, Groupement Hospitalier NordHospices Civils de LyonLyonFrance
  2. 2.EMR3738, Faculté de médecine Lyon-sudUniversité Lyon 1LyonFrance
  3. 3.Faculté de pharmacieUniversité Lyon 1LyonFrance
  4. 4.UMR CNRS 5558, Laboratoire de Biométrie et Biologie EvolutiveUniversité Lyon 1LyonFrance
  5. 5.Pharmacie, Institut d’Hématologie et d’Oncologie PédiatriqueHospices Civils de LyonLyonFrance

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