A multicompartment stomach physiologically-based pharmacokinetic model capturing gastric reacidification can improve food effect predictions of weak bases

Various changes within the gastrointestinal tract following meal intake may significantly impact oral drug absorption. Physiologically-based pharmacokinetic (PBPK) models are often used to perform early predictions of food effects on oral absorption. However, the stomach compartment within these physiological models does not wholly reflect physiology of the fed state. The current approach where the stomach compartment is fixed at pH 5 overlooks the changing gastric pH profile over time after food consumption. We suggest the integration of a multicompartment stomach that represents the various pH phases of the fed stomach to better capture ionizable drug dissolution. Ibuprofen sodium (weak acid) and posaconazole (weak base) were investigated to determine whether a PBPK model that could better capture the varying gastric pH would yield an improvement in food effect predictions. The one-compartment and multicompartment stomach models' simulations for ibuprofen sodium exposure with and without food consumption were comparable. For posaconazole, the one-compartment stomach model predicted a smaller area under the curve and lower maximum plasma concentration than the multicompartment stomach model's output in the fed state. Although both models accurately predicted a positive food effect, the magnitude of the simulated fed to fasted fold-changes in posaconazole exposure by the one-compartment stomach model was much less than observed fold-changes. These results suggest that a multicompartment stomach model featuring gastric re-acidification associated with food intake should be incorporated for more accurate food effect predictions for weakly basic compounds.