1 Pharmaceutical Design and Drug Delivery, Department of Pharmacy, Faculty of Health and Medical Sciences, Københavns Universitet2 IKVH Fysiologi og ernæring samt pelsdyrfarmen, Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, Københavns Universitet3 Department of Pharmacy, Uppsala University, Sweden.4 Censorship, Faculty Service, Faculty of Pharmaceutical Sciences, Københavns Universitet5 Biologics and Pharmaceutical Sciences, H. Lundbeck A/S, Copenhagen, Denmark.6 AstraZeneca Pharmaceutics, R&D, Mölndal, Sweden.7 Pharmaceutical Design and Drug Delivery, Department of Pharmacy, Faculty of Health and Medical Sciences, Københavns Universitet8 Censorship, Faculty Service, Faculty of Pharmaceutical Sciences, Københavns Universitet
The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000mL or 100mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533mL or 105mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro-in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo-in vitro-in silico correlations for Cmax, were obtained with in silico predictions utilizing a 105mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100mL fasted state simulated media.
International Journal of Pharmaceutics, 2014, Vol 473, Issue 1-2, p. 356-365