Aim: A method for transporter-based in vitro-in vivo extrapolation (IVIVE) was previously developed and demonstrated by predicting valsartan PK after i.v.administration . The purpose of this study was to (1) extend the model to describe valsartan PK in human after p.o.administration, and (2) explore the utility of the model to predict valsartan PK in pediatric populations.
Methods: An absorption/PBPK model for valsartan PK was developed using GastroPlus™ 8.5 (Simulations Plus, Inc.). The program’s Advanced Compartmental Absorption and Transit (ACAT™) model described the absorption of the drug, while PK was simulated with its PBPKPlus™ module. Physiologies were generated by the program’s internal Population Estimates for Age-Related (PEAR™) Physiology™ module. Intestinal absorption and tissue distribution accounted for both passive diffusion and carriermediated transport. Total clearance consisted of biliary (major) and renal (minor) secretion. Passive diffusion between the extracellular and intracellular spaces in all tissues was calculated from specific permeability-surface area product (SpecPStc) and tissue cell volumes. SpecPStc along with the carriermediated transport kinetics in liver and kidney was predicted from previously reported in vitro measurements . Passive renal secretion was estimated as Fup*GFR. Plasma protein and red blood cell binding was adjusted to account for pediatric plasma protein levels and hematocrit. The effect of intestinal MRP2 on valsartan absorption was included in the model. Model parameters (Vmax for liver, kidney and intestinal transporters, and SpecPStc) were also fitted against Cp-time profiles after i.v. and p.o. administration in adults , and the refined model was used to predict pediatric PK .
American Association of Pharmaceutical Scientists (AAPS), November 10-14, 2013, San Antonio, TX
By Viera Lukacova, Michael B. Bolger, Walter S. Woltosz