Impact of prandial state on luminal and permeation-behavior of fosamprenavir oral suspension studied by in vitro tools: Solubility-, bioconversion- and permeation- studies in biomimetic media

Fosamprenavir is a prodrug designed to overcome the solubility challenge of the parent drug amprenavir, a protease inhibitor. For the marketed oral suspension (Telzir®) a clinically documented negative food effect has been reported. The present study aims to gain a better mechanistic understanding of the food effect by in vitro tests on solubility, bioconversion, permeability, and dynamic dissolution/bioconversion/permeation studies in a high throughput manner on a microtiter plate (Permeapad® Plate). In order to mimick luminal condition changes in connection with food, various modified versions of fasted and fed state simulated intestinal fluids (FaSSIF-V2) and (FeSSIF–V2) were used. The kinetics of enzymatic cleavage (simulated bioconversion) were studied in these media with a focus on molecularly dissolved drug concentrations using microdialysis. Dynamic dissolution/bioconversion/permeation experiments, indicated the following factors to contribute to reduced permeation in fed state: elevated inorganic phosphate concentrations, higher concentrations of bile salts and lipids and lower intestinal pH. The impact of these effects is difficult to capture in vivo due to their interconnection and large variability between individuals. This study revealed factors leading to an altered luminal behavior of Telzir® oral suspension in fed state, which may contribute to explain the observed reduced amprenavir absorption from the suspension. Especially the high throughput small-scale dissolution/bioconversion/permeation experiments on a microtiter plate were demonstrated an efficient and powerful tool for elucidating the food effects of phosphate-ester prodrug type drug products as far as their altered luminal behavior is concerned.