A physiologically relevant fed gastric pH profile improves the prediction of food effects

Food intake may significantly influence oral drug pharmacokinetics, primarily through changes in gastric pH, increased gastric emptying time, and the presence of fats and bile salts in the small intestine. Physiologically-based pharmacokinetic (PBPK) models can be leveraged to evaluate potential food effects by comparing simulated exposure parameters in the fed and fasted states. The incorporation of a more physiologically relevant, dynamic fed gastric pH profile into a PBPK model was evaluated for its impact on the performance of food effect predictions. Two models that capture changes in fed gastric pH over time were proposed: the multi-compartment stomach (MCS) and the dynamic one-compartment stomach (DOCS) models. Using the MCS and DOCS models, the predicted food effect of three compounds with pH-dependent solubility were compared to those obtained using the conventional approach of setting the fed gastric pH at a static pH 5 (termed the static one-compartment [SOCS] model). The MCS and DOCS PBPK models were successful in predicting the observed food effect of ibuprofen sodium, itraconazole, and posaconazole. In contrast, the SOCS model could predict the correct observed effect of food for ibuprofen sodium and posaconazole but misassigned the food effect for itraconazole. In general, the MCS and DOCS models offered better performance when predicting food effects when compared to the conventional approach. These results indicate that a dynamic fed gastric pH profile in PBPK models can improve model performance when investigating food effects of ionizable compounds.