Food Effect Projections via Physiologically Based Pharmacokinetic Modeling: Predictive Case Studies

Abstract Food can alter the absorption of orally administered drugs. Biopharmaceutics physiologically based pharmacokinetic (PBPK) modeling offers the possibility to simulate a compound's pharmacokinetics under fasted or fed states. To advance the utility of PBPK modeling, with a view to regulatory impact, we have pooled our experience across four pharmaceutical companies to propose a general multi-step PBPK workflow leveraging pre-existing clinical data for immediate release formulations of BCS I and BCS II compounds. With this strategy, we wish to promote pragmatic PBPK approaches for compounds where absorption is well understood, i.e. compounds with moderate to high permeability that are not substrates for uptake transporters. Five case studies demonstrate how food effect can be well predicted using appropriately established and validated models. The case studies integrate solubility and/or dissolution data for initial model development and apply a "middle-out" validation with clinical data in one prandial state. Then, whenever possible, a validation against both fasted and fed state data is recommended prior to application of the models prospectively for to-be-marketed formulations. Thus, when combined with limited clinical data, PBPK models could be used to simulate outcomes for new doses, formulations, or API forms, in lieu of a clinical food effect study.