Risk of Hematologic Events With Coadministration of Methotrexate and the Breast Cancer Resistance Protein Inhibitor Febuxostat

Background: The breast cancer resistance protein (BCRP) is a key drug transporter found in the liver, kidney, central nervous system, and gastrointestinal tract. Due to the wide expression of BCRP, interactions of other drugs with methotrexate (MTX) may differ in oral and intravenous MTX users, and understanding of these interactions may be useful in preventing severe adverse events. Febuxostat, a urate-lowering drug, inhibits BCRP. Objective: The objective of this study was to clarify the differences in the drug-drug interaction profiles of oral and intravenous methotrexate, associated with BCRP. Methods: We analyzed the Japanese Adverse Drug Event Report database and compared the frequency of hematologic events in patients taking oral and intravenous MTX, with or without the concomitant use of febuxostat or allopurinol. Hematologic events were defined as pancytopenia and neutropenia. Multiple logistic regression analysis was then used to identify the risk factors for hematologic events in oral and intravenous MTX users. Results: We identified 8 453 oral and 810 intravenous MTX users with 546 and 126 cases of hematologic events, respectively. Compared with those not using febuxostat, a disproportionate number of hematologic events was observed in intravenous MTX users concomitantly using febuxostat (P < 0.01). The multivariate logistic analysis of intravenous MTX users showed that hematologic events were significantly associated with febuxostat use (P < 0.01) and age ≥ 60 years (P < 0.01). Conclusion and Relevance: Our findings suggest that patients being treated with intravenous MTX who concomitantly use febuxostat may be at an increased risk of hematologic events, presumably due to BCRP-mediated drug-drug interaction.