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

Abstract

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™. 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.

• CYP3A
• drug–drug interaction
• P-glycoprotein

Acknowledgements

The authors would like to thank Mr. Hiroshi Sugimoto, Dr. Yuu Moriya, Mr. Takuya Ebihara and Mr. Nobuyuki Amano at Takeda Pharmaceutical Company Limited for many helpful discussions.