Abstract

Objectives: Fluconazole is an antifungal agent widely used in the clinical setting for the treatment of candidiasis and meningitis. It undergoes minimal metabolism and is excreted renally(1). Fluconazole is a moderate dose-dependent inhibitor of CYP3A4, CYP2C9 and CYP2C19. Saturable hepatic binding is a major determinant of the volume of distribution of fluconazole and the main reason for its nonlinearity. The liver:plasma partition coefficient (Kp) for fluconazole was shown to be concentration-dependent and ranged from 2 to 30 in rat studies(2). The aim of our study was to predict human pharmacokinetics of fluconazole and the magnitude of its DDIs using physiologically based pharmacokinetics (PBPK), and to test the applicability of concentration-dependent experimental liver Kps for that purpose.

Methods: GastroPlus™ (Simulations Plus, Inc.) was used to build PBPK models of fluconazole’s distribution and clearance in humans using intravenous (IV) and oral Cp-time profiles for 100 mg(3,4) and 400 mg(5) doses obtained from the literature. Experimental (rat) Kps were used for drug partitioning between liver:plasma and kidney:plasma, while a modified Rodgers and Rowland predictive method based upon drug properties and tissue composition was applied to calculate Kps for all other tissues. Clearance was fitted to the IV data using the PKPlus™ module in GastroPlus. ADMET Predictor™ (Simulations Plus, Inc.) was used to predict human intestinal permeability for fluconazole. DDIs were predicted using a test version of a steady state DDI Module in GastroPlus that is currently under development.

International Conference on Drug-Drug Interactions (DDI), June 2009, Seattle, Washington

By Grazyna Fraczkiewicz, Neil Parrott, Viera Lukacova, Michael Bolger, John Crison, Walter Woltosz, & Thierry Lave