Physiologically-Based Model for Fluvoxamine Disposition and Prediction of Drug-Drug Interactions
Fluvoxamine absorption and pharmacokinetics were simulated using GastroPlus™ 6.0 (Simulations Plus, Inc.). The program’s Advanced Compartmental and Transit model described the absorption; pharmacokinetics was simulated with a physiologically-based pharmacokinetics model. Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related Physiology™ module. Where available, human tissue/plasma partition coefficients (Kps) were approximated with experimental human Kps for a similar drug, fluoxetine. Remaining Kps were predicted in GastroPlus from drug properties and tissue composition using a modified version of a method based on equations published by Rodgers & Rowland. Clearance was fitted to plasma concentration-time profiles of fluvoxamine after oral dosing reported in literature. The final model accurately reproduced in vivo plasma concentration-time profiles in human for solution and solid oral doses over the range of 25-100 mg. Simulated plasma and liver concentrations were used in predictions of drug-drug interactions using steady-state models. Experimental values for in vitro and in vivo inhibition constants were reported in literature for CYP 1A2 and 2C19, suggesting higher inhibition potency of fluvoxamine in vivo than in vitro against both enzymes. However, when these Kis were combined with the relevant simulated concentrations (in vitro Ki with liver concentration and in vivo Ki with plasma concentration), both were able to predict fluvoxamine inhibition effect on CYP 1A2 and 2C19 substrates.
International Conference on Drug-Drug Interactions (DDI), June 2009, Seattle, Washington
John Chung, Viera Lukacova, Neil J. Parrott, Walter Woltosz, Michael Bolger