PII-029 - THE EFFECTS OF RIFAMPICIN AS AN ORGANIC ANION TRANSPORTING POLYPEPTIDES INHIBITOR AND FEBUXOSTAT AS A BREAST CANCER RESISTANCE PROTEIN INHIBITOR ON PHARMACOKINETICS OF METHOTREXATE IN HEALTHY SUBJECTS.

S. Hwang¹, Y. Lee², J. Cho³, H. Lee⁴, S. Yoon³, J. Chung³; ¹Seoul National University Hospital, Seoul, Republic of Korea, ²Seoul National University, Seoul, Republic of Korea, ³Seoul National University Bundang Hospital, Seoul, Republic of Korea, ⁴Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Background: Methotrexate is an antifolate agent used in the treatment of cancer and autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. A single dose of rifampicin inhibits organic anion transporting polypeptides (OATP1B1 and 1B3). Febuxostat was recently found to inhibit breast cancer resistance protein (BCRP) in vitro. This study investigated the effects of rifampicin and febuxostat on methotrexate pharmacokinetics (PK).

Methods: A randomized, open-label, 4-treatment, 6-sequence, 4-period crossover study was conducted in healthy Korean subjects. Subjects received each treatment according to the assigned sequence, and 4-treatments were a single dose of methotrexate 2.5 mg alone, co-administration of methotrexate and a single dose of rifampicin 600 mg, febuxostat 80 mg, or both. Blood samples for PK analysis were collected up to 24 hours postdose. PK parameters of methotrexate co-administered with rifampicin or febuxostat or both were compared to those administered alone.

Results: A total of 13 subjects were enrolled and 11 subjects completed the study. When methotrexate was co-administered with rifampicin or rifampicin and febuxostat, the maximum concentration (Cmax) of methotrexate increased by 40% and 42%. However, the Cmax of methotrexate when co-administered with febuxostat was similar. The systemic exposure of methotrexate when co-administered with rifampicin, febuxostat, or both increased by approximately 33%, 17%, and 52%, respectively, compared to those when administered alone.

Conclusion: OATP inhibition by rifampicin increased the systemic exposure of methotrexate. Febuxostat showed the potential for BCRP inhibition. Co-administration of rifampicin and febuxostat may have additive effects on the increasing systemic exposure of methotrexate by OATP and BCRP inhibition.