Integration of in vitro binding mechanism into the semiphysiologically based pharmacokinetic interaction model between ketoconazole and midazolam.
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 of ketoconazole 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.
1] Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA [2] Indiana Institute of Personalized Medicine, Indiana University School of Medicine, Indianapolis, IN, USA [3] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
Sara K
SK
Quinney
Procept Partners, Plainfield, IN, USA.
Shawn
S
Knopp
Department of Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
Chien
C
Chang
Eli Lilly and Company, Indianapolis, IN, USA.
Stephen D
SD
Hall
1] Indiana Institute of Personalized Medicine, Indiana University School of Medicine, Indianapolis, IN, USA [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Lang
L
Li