Abstract

Purpose: To optimize a PBPK model of omeprazole for prediction of DDIs with respect to polymorphic expression of CYP enzymes.

Methods: Omeprazole absorption and pharmacokinetics were simulated using GastroPlusTM 6.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental and Transit (ACAT) model described the absorption of the drug, while pharmacokinetics was simulated with its PBPKPlus™ module. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™ module. Tissue/plasma partition coefficients were calculated using a modified Rodgers algorithm based on tissue composition and in vitro and in silico physicochemical properties (ADMET Predictor™, Simulations Plus, Lancaster, CA). The metabolic clearance of omeprazole in gut and liver was based on in vitro enzyme kinetic constants for CYP3A4, 2C9 and 2C19 combined with built-in in vitro values for the distribution of 3A4 in gut and the average expressions of all three enzymes in liver. A test version of the upcoming DDI Module in GastroPlus was used to predict the DDIs with different drugs.

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

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