Predicting Food Effect On Oral Drug Absorption For Solubility-Epithelial Membrane Permeation-Limited Cases With Bile Micelle Solubilization

Purpose The purpose of this study was to investigate the theoretical and in vitro experimental prediction of food effects on oral drug absorption, focusing on solubility-epithelial membrane permeation-limited cases (SL-E). Method Bosentan, fidaxomicin, pranlukast, and rifaximin were employed as model SL-E drugs. Celecoxib and danazol were employed as solubility-unstirred water layer permeation-limited cases (SL-U) for comparison. Theoretical predictions of food effects were based on the rate-limiting steps of the fraction of a dose absorbed ( Fa ) (FaRLS) (Fa rate-limiting step). μFLUX was used as a dissolution-permeation flux ( J μFLUX ) experiment. Fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, respectively) were employed as the donor solution. Results For all SL-E drugs, the food effect on Fa was theoretically predicted to be 1.2, irrespective of bile micelle solubilization (FaSSIF/FeSSIF: bosentan (2.1), fidaxomicin (2.3), pranlukast (9.1), and rifaximin (3.5)). Theoretically, an increase in solubility by bile micelles is counterbalanced by a decrease in effective permeability ( P eff ) due to a decrease in the free fraction ( P eff is defined based on unbound + bound drug concentration ( C D )). This prediction was consistent with the clinical data (fed/fasted AUC ratio: 1.1, 1.0, 1.3, and 1.6, respectively). In μFlux, even though C D was markedly higher in FeSSIF than in FaSSIF (1.9, 3.1, 20, and 3.3-fold, respectively), J μFLUX was less enhanced (0.91, 0.81, 2.4, and 0.81-fold, respectively). For the SL-U drugs, as theoretically expected, J μFLUX was increased as C D was increased, which was consistent with the clinical data. Conclusion FaRLS appropriately predicted the food effect for the SL-E drugs. The mechanism was experimentally confirmed by μFlux.