Clarification of P-glycoprotein inhibition-related drug-drug interaction risks based on a literature search of the clinical information

1. Recently, the Food and Drug Administration (FDA) and European Medicines Agency have shown decision trees to determine whether a drug candidate is an inhibitor of P-glycoprotein (P-gp). However, there has been no clear information on whether P-gp inhibition can be significant in clinical drug-drug interactions (DDIs). The purpose of this study was to confirm the effect of P-gp inhibition through comprehensive analysis of the clinical DDI studies. 2. Clinical information on P-gp inhibition was collected using the University of Washington Metabolism and Transport Drug Interaction Database (TM). The risks of P-gp inhibition-related DDI were qualitatively evaluated in terms of the contribution of CYP3A inhibition. The degrees of DDI risk were categorized using the area under the plasma concentration-time curve increase ratio (AUCR), according to the FDA DDI criteria. 3. When both P-gp and CYP3A were inhibited, the DDI risks were potent in 25% of the studies. When CYP3A inhibition did not contribute to the DDI, no study was categorized as potent DDI risk, and the detailed analysis revealed that AUCRs were basically <3.0. The DDI risk caused by P-gp inhibition solely would be limited, although the use of P-gp substrates with narrow therapeutic range should be carefully controlled.