Predicting pharmacokinetic food effects using biorelevant solubility media and physiologically based modelling

Background: Food-induced changes in gastric emptying time, gastric pH and/or intestinal fluid composition may have an impact on the pharmacokinetics of drugs. The aim of this work was to use mathematical models describing physiology in fed and fasted states together with biorelevant solubility and degradation data to simulate food effects for six compounds from recent Roche projects. Methods: The solubility of each compound was measured in different biorelevant media: simulated human gastric fluid for the fasted and fed state, simulated human intestinal fluid for the fasted, fed and high-fat state, and simulated human colonic fluid for the upper and the lower colon. A physiologically based absorption model was developed in GastroPlus (TM) for each compound using permeability, solubility, metabolism and distribution data. By incorporating the appropriate physiological parameters and solubility data into the model, the oral pharmacokinetics of each drug was simulated under fasted, fed and/or high-fat conditions. Predicted and observed plasma concentration-time profiles and food effects were compared for a range of doses to assess the accuracy of the simulations. Results: The models were able to distinguish between minor and significant food effects. The simulation captured well the magnitude of the food effects and for the six compounds correctly predicted the observed plasma exposure in fasted, fed and high-fat conditions. Conclusion: Biorelevant solubility tests can be used together with physiologically based absorption models to predict clinical food effects caused by solubility and/or dissolution rate limitations.