Gonzalez-GarcÃa, I. (1), Mangas-Sanjuan,V.(2), Bermejo, M.(2), Casabo, VG.(1)
(1) Departamento de Farmacia y TecnologÃa Farmacéutica, Universidad de Valencia;(2) Departmento de IngenierÃa, Universidad Miguel Hernández de Elche.
Introduction: Fexofenadine HCl (FEX), a second generation non-sedating histamine H1 receptor antagonist, is an active metabolite of terfenadine. Permeability of FEX was determined in an in vitro cell model and in situ experiment at different donor concentrations, and the effect of sodium dodecyl sulfate (SDS) at two concentration levels (10 and 50 µM) on FEX permeability was evaluated simultaneously.
Objective: The aim of this work is to model simultaneously in vitro and in situ data to obtain common parameters of the absorption and distribution of Fexofenadine in both biological systems.
Materials and Methods: The in vitro transport studies were developed in Caco-2 cell in apical-to-basolateral (AB) and basolateral-to-apical (BA) direction. The in situ experiments were performed in Wistar rats. Permeability values were estimated by non-linear regression of cumulative amounts in the receptor chamber, and remaining amounts in donor chamber versus time and by non-linear regression of decreasing concentrations in lumen. The fitting procedures were performed using NONMEM 7.2 with FOCE+I for objective function estimation and ADVAN9 subroutine. Several kinetic models were fitted to the data, functional and mechanistic models, selecting the best model with lowest objective function value. The inter-individual and residual variabilities of the kinetic parameters were described with exponential models. Goodness of fit plots and visual predictive check were generated to confirm the final model.
Results: The simultaneous analysis of in vitro and in situ experiments are well modeled using a common permeability for all concentrations without surfactant and a different permeability in the presence of surfactant. An active transport is observed in cells and in rats which was included in the final model. The presence of high concentration of surfactant (50 mM) affects to the passive diffusion of FEX in cells systems. Nevertheless, the presence of surfactant does not affect in vivo, but changes the function of the transport. Permeability as a function of time and lag time parameters were used to account for the intercept of the cumulative fractions permeated versus time that was different from 0.
Conclusions: Fexofenadine has a low intestinal permeability in vitro in Caco-2 cells and in situ rats experiments and the transport of the drug is concentration-dependent. The simultaneous analysis allows to estimate parameters that are present in both systems and to be able to establish similarities or differences between the cell line and rats.
Reference: PAGE 22 () Abstr 2738 [www.page-meeting.org/?abstract=2738]
Poster: New Modelling Approaches