Theoretical considerations on quantitative prediction of drug-drug interactions.

The prediction of drug-drug interactions (DDIs) associated with change in clearance for metabolism is reviewed, particularly focusing on pharmacokinetic theories for prediction based on in vitro and in vivo observation. First, there is discussion about how quantitative determination of the contribution of major clearance pathways is fundamental for the accurate prediction of DDIs. Secondly, the concentrations of causative drugs at sites of interactions are discussed. Although DDIs have been predicted from in vitro pharmacokinetic parameters based on predicted hepatic unbound concentrations of inhibitors and inducers, there are noticeable discrepancies between predicted and observed magnitudes of these DDIs. To solve these issues, a method for the prediction of unbound hepatic concentration is proposed based on theoretical considerations. Finally, a pharmacokinetic model to describe the intestinal first pass metabolism is considered, particularly focusing on the importance of the Q(gut) model. Although this Q(gut) model was proposed as an empirical model, theoretical considerations suggest that the model is regarded as a physiologically-based pharmacokinetic model that can predict significance of intestinal DDIs. Theoretical considerations proposed in the present article may be helpful for future analysis of DDIs.