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Jan 1, 2009
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Azole Antifungals: Physiologically-Based Pharmacokinetic (PBPK) Modeling and Prediction of Drug-Drug Interactions (DDIs)

Abstract

Purpose: Develop PBPK models for azole antifungals for prediction of DDIs.

Methods: The absorption and pharmacokinetics of azole antifungals were simulated using GastroPlus™ 6.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental and Transit (ACAT) model described the absorption and intestinal first pass extraction of the drugs, while pharmacokinetics was simulated with a PBPK model. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™. Experimental tissue/plasma partition coefficients (Kps) were used where available. A modified Rodgers algorithm [1,2) based on tissue composition and in vitro and in silica physicochemical properties from ADMET Predictor™ 4.0 (Simulations Plus, Inc., Lancaster, CA) were used to estimate the remaining Kps. Metabolic clearances in gut and liver were estimated from in vitro enzyme kinetic constants for relevant enzymes combined with built-in in vitro values for the distribution of 3A4 in gut [3], and the average expressions of all relevant enzymes in liver [4). A test version of a new DDI Module in GastroPlus was used to predict the DDIs of azole antifungals with different drugs.

By Grace Fraczkiewicz, Viera Lukacova, N. J. Parrott, Michael B. Bolger, Walter S. Woltosz

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