Integration of in vitro binding mechanism into the semiphysiologically based pharmacokinetic interaction model between Ketoconazole and Midazolam

Sara K. Quinney, Shawn Knopp, Chien Chang, Stephen D. Hall, Lang Li

Research output: Contribution to journalReview article

1 Scopus citations

Abstract

In vitro screening for drug-drug interactions is an integral component of drug development, with larger emphasis now placed on the use of in vitro parameters to predict clinical inhibition. However, large variability exists in Ki reported for ketoconazole with midazolam, a model inhibitor-substrate pair for CYP3A. We reviewed the literature and extracted Ki for ketoconazole as measured by the inhibition of hydroxymidazolam formation in human liver microsomes. The superset of data collected was analyzed for the impact of microsomal binding, using Langmuir and phase equilibrium binding models, and fitted to various inhibition models: competitive, noncompetitive, and mixed. A mixed inhibition model with binding corrected by an independent binding model was best able to fit the data (Kic = 19.2 nmol/l and Kin = 39.8 nmol/l) and to predict clinical effect ofketoconazole on midazolam area under the concentration-time curve. The variability of reported Ki may partially be explained by microsomal binding and choice of inhibition model.

Original languageEnglish (US)
Article numbere75
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume2
Issue number9
DOIs
StatePublished - Sep 1 2013

ASJC Scopus subject areas

  • Modeling and Simulation
  • Pharmacology (medical)

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