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

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

Research output: Contribution to journalArticle

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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
Article numbere75
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume2
Issue number9
DOIs
StatePublished - Sep 2013

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Midazolam
Ketoconazole
Pharmacokinetics
Cytochrome P-450 CYP3A
Preclinical Drug Evaluations
Liver Microsomes
Drug Interactions
Interaction
Drugs
Drug interactions
Model
Pharmaceutical Preparations
Predict
Phase Equilibria
Phase equilibria
Liver
Inhibitor
Screening
In Vitro Techniques
Substrate

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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Integration of in vitro binding mechanism into the semiphysiologically based pharmacokinetic interaction model between Ketoconazole and Midazolam. / Quinney, Sara; Knopp, Shawn; Chang, Chien; Hall, Stephen D.; Li, Lang.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 2, No. 9, e75, 09.2013.

Research output: Contribution to journalArticle

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