Physiologically Based Model for Ketoconazole Disposition and Prediction of its Drug-Drug Interactions
Objectives: Ketoconazole is a potent inhibitor of the major drug-metabolizing enzyme, CYP3A4 and, as the result of that, is involved in many drug-drug interactions. Pharmacokinetic (PK) information available for ketoconazole is limited since no intravenous human study is available to date, which probably contributes to the lack of published comprehensive PK models for this drug. The aim of our study was to predict human PK of ketoconazole and the magnitude of its drug-drug interactions (DDIs) using physiologically based pharmacokinetics (PBPK).
Methods: GastroPlus™ (Simulations Plus, Inc.) was used to build PBPK models of ketoconazole’s distribution and clearance in humans from oral Cp-time profiles for 200, 400, 600 and 800 mg doses obtained from the literature. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™. The program’s modified Rodgers and Rowland predictive method based upon drug properties and tissue composition was used to calculate Kps for all tissues. Nonlinear clearance was fitted to oral doses with the program’s PKPlus™ module using Michaelis-Menten kinetics. ADMET Predictor™ (Simulations Plus, Inc.) was used to predict human intestinal permeability for ketoconazole. DDIs were predicted using a test version of a new steady state DDI Module in GastroPlus.
16th North American ISSX Meeting, October 18-22, 2009, Baltimore, MD
By Grazyna Fraczkiewicz, Viera Lukacova, Neil Parrott, Michael B. Bolger, John R. Crison, Walter S. Woltosz, & Thierry Lave