Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug-Drug Interactions on Metabolizing Enzymes and Transporters

A general objective of drug-drug interaction (DDI) studies is to determine whether potential interactions of new molecular entities with concomitantly administered other drugs exist and, if DDIs occur, whether dosage adjustments are required. A typical end point for DDI evaluations is the ratio of area under the plasma concentration-time curve (AUC) of substrate drugs (AUCR), whereas the ratios of maximal plasma concentration (C-max) and terminal half-life (t(1/2)) are also important to understand DDI mechanisms (CmaxR and t(1/2)R, respectively). Because changes in substrate AUC by precipitant drugs ultimately result from alterations of C-max and t(1/2), AUCR can be considered a hybrid parameter of CmaxR and t(1/2)R, for example, AUCR approximate to CmaxR x t(1/2)R. The primary objective of this study was to investigate the relationships between AUCR, CmaxR, and t(1/2)R in physiologically based pharmacokinetic model-predicted and clinically observed DDI results. First, the model-predicted results showed the excellent proportional relationship between AUCR and (C(max)Rxt(1/2)R) in DDI results of virtual substrates having a wide range of oral bioavailability with coadministration of ketoconazole, ritonavir, and rifampin. Second, the reasonable proportional relationships were also observed in the clinically observed DDI results of midazolam and statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) with various inhibitors and inducers. Finally, these results suggest that utilization of the proportional relationship between AUCR and (CmaxR xt(1/2)R) can provide an additional framework to further interpret DDI results reasonably and clearly. Furthermore, the proportional relationship can be purposely used to assess study design and pharmacokinetic analyses in DDI studies.