Purpose: To optimize a PBPK model to describe saquinavir absorption and pharmacokinetics (PK) and with it, predict the effect of saquinavir on midazolam PK.
Methods: Absorption and PK of both drugs were simulated using GastroPlus™ 7.0 (Simulations Plus, Inc., Lancaster, CA). The program’s Advanced Compartmental Absorption and Transit (ACAT™) model described the intestinal absorption and gut first-pass extraction (FPE), coupled with its PBPKPlusTM module for simulation of the PK distribution, liver FPE and systemic clearance. Human physiologies were generated by the program’s internal Population Estimates for Age-Related (PEAR) Physiology™ module. Tissue/plasma partition coefficients were calculated using our modified Rodgers algorithm  based on tissue composition and in vitro and in silico (ADMET Predictor™ version 5.5, Simulations Plus, Inc., Lancaster, CA) physicochemical properties. Metabolic clearances of both drugs in gut and liver were based on in vitro enzyme kinetic constants for 3A4 from literature [2,3]. The PBPK model utilized built-in values for the expression levels of 3A4 in each gut enterocyte compartment as well as the average expression of 3A4 in liver. The effect of intestinal P-gp on saquinavir absorption was incorporated in the model with Km and Vmax values fitted to in vivo data. The PBPK models correctly described plasma concentration-time profiles of midazolam and saquinavir for various doses after i.v. and p.o. administration. The validated PK models were then used in dynamic simulations in the GastroPlus 7.0 DDI Module to predict the effect of CYP 3A4 deactivation by saquinavir on midazolam PK.
American Association of Pharmaceutical Scientists (AAPS), October 23-27, 2011, Washington, D.C.
By Viera Lukacova, Walter S. Woltosz, Michael B. Bolger