PBPK Modeling of Fluoxetine and its Metabolite Norfluoxetine: Prediction of the Extent of Their Involvement in Drug Interactions

Authors: Fraczkiewicz G, Lukacova V, Parrott N, Bolger MB, Crison JR, Woltosz WS, Lavé T
Conference: AAPS
Keywords: ADMET, Cp-Time, DDIs, drug-drug interactions (DDIs), fluoxetine, norfluoxetine, PBPK, tissue:plasma
Software: ADMET Predictor®, GastroPlus®
Division: PBPK

Abstract

Objectives: The aim of our study was to simulate the human pharmacokinetics of fluoxetine and its major metabolite, norfluoxetine, and predict the magnitude of their drug-drug interactions (DDIs) using physiologically based pharmacokinetics (PBPK).

Methods: GastroPlus™ (Simulations Plus, Inc.) was used to build PBPK models of fluoxetine and norfluoxetine in humans using plasma concentration-time (Cp-time) profiles for 20, 40, and 60 mg oral (PO) doses obtained from the literature[1, 2, 3]. Experimental postmortem human tissue:plasma partition coefficients (Kps) were used for drug partitioning into the following tissues: liver, lungs, kidney, spleen, brain, and heart[4]. Kps for all other tissues were calculated using a modified Rodgers and Rowland method based upon drug properties and tissue compositions. in vitro Km and Vmax values were used to describe the metabolic clearance of fluoxetine and formation of its major metabolite, norfluoxetine[5]. ADMET Predictor™ (Simulations Plus, Inc.) was used to predict human intestinal permeability for both compounds. DDIs were predicted using a test version of an upcoming DDI Module in GastroPlus using the steady-state option.

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

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