A Bayesian meta-analysis on published sample mean and variance pharmacokinetic data with application to drug-drug interaction prediction

Menggang Yu, Seongho Kim, Zhiping Wang, Stephen Hall, Lang Li

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

In drug-drug interaction (DDI) research, a two-drug interaction is usually predicted by individual drug pharmacokinetics (PK). Although subject-specific drug concentration data from clinical PK studies on inhibitor or inducer and substrate PK are not usually published, sample mean plasma drug concentrations and their standard deviations have been routinely reported. Hence there is a great need for meta-analysis and DDI prediction using such summarized PK data. In this study, an innovative DDI prediction method based on a three-level hierarchical Bayesian meta-analysis model is developed. The three levels model sample means and variances, between-study variances, and prior distributions. Through a ketoconazle-midazolam example and simulations, we demonstrate that our meta-analysis model can not only estimate PK parameters with small bias but also recover their between-study and between-subject variances well. More importantly, the posterior distributions of PK parameters and their variance components allow us to predict DDI at both population-average and study-specific levels. We are also able to predict the DDI between-subject/study variance. These statistical predictions have never been investigated in DDI research. Our simulation studies show that our meta-analysis approach has small bias in PK parameter estimates and DDI predictions. Sensitivity analysis was conducted to investigate the influences of interaction PK parameters, such as the inhibition constant Ki, on the DDI prediction.

Original languageEnglish (US)
Pages (from-to)1063-1083
Number of pages21
JournalJournal of biopharmaceutical statistics
Volume18
Issue number6
DOIs
StatePublished - Nov 1 2008

Keywords

  • Area under the concentration curve ratio (AUCR)
  • Bayesian hierarchical model
  • Drug-drug interaction (DDI)
  • Meta-analysis
  • Monte Carlo Markov chain (MCMC)
  • Pharmacokinetics (PK)
  • Prediction

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Statistics and Probability

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