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Nov 8, 2009
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Modeling Fluconazole – a Case with Concentration-Dependent Liver:Plasma Partition Coefficient

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) 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 using physiologically based pharmacokinetics (PBPK) and to test the applicability of static 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 (PO) Cp-time profiles for 100 mg(3,4) and 400 mg(5) doses obtained from the literature. The models were based on human physiologies for 69 kg and 72 kg males, reflecting mean body weights of subjects in studies with 100 mg and 400 mg PO doses, respectively. Experimental liver:plasma and kidney:plasma Kps obtained from rat were used. A modified Rodgers and Rowland method based upon drug properties and tissue composition was used 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 the studied compound.

American Association of Pharmaceutical Scientists (AAPS), November 8-12, 2009, Los Angeles, CA

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

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