Dynamic Changes in Gastrointestinal Fluid Characteristics after Food Ingestion Are Important for Quantitatively Predicting the In Vivo Performance of Oral Solid Dosage Forms in Humans in the Fed State

The aim of this study was to develop a simulation model to predict the in vivo performance of solid oral dosage forms in humans in the fed state. We focused on investigating the effect of dynamic changes in gastrointestinal (GI) fluid characteristics in the fed state on the in vivo performance of solid dosage forms. We used six solid dosage forms containing weak base drugs as model formulations, two with positive food effects in humans, two with negative food effects, and two which are not affected by food ingestion. These model drug formulations were used to perform biorelevant dissolution tests in the stomach and small intestine under both prandial states. The in vitro properties of the drug products obtained from these tests were then coupled with in silico models (fasted or fed) to predict food effects in humans. We successfully incorporated the dynamic changes in GI fluid characteristics and their effects on the in vivo dissolution of drugs into the prediction model for the fed state. This newly designed physiologically based biopharmaceutics modeling approach provided the precise and quantitative prediction of food effects (i.e., changes in C_max and AUC after food ingestion) in humans while considering the dynamic changes in fluid characteristics in the fed state.

biorelevant dissolution; food effect; gastrointestinal tract; in silico modeling and simulation; solid formulation; weak base drug.