A drug–drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers

PURPOSE: Peficitinib is an oral pan-Janus kinase inhibitor for the treatment of rheumatoid arthritis. Co-administration of peficitinib with metformin, a type 2 diabetes therapy, can occur in clinical practice. Hepatic and renal uptake of metformin is mediated by organic cation transporter 1 (OCT1) and OCT2, respectively, and its renal excretion by multidrug and toxin extrusion 1 (MATE1) and MATE2-K. This study investigated the effect of peficitinib on metformin pharmacokinetics in vitro and in healthy volunteers. METHODS: Inhibitory effects of peficitinib and its metabolite H2 on metformin uptake into human OCT1/2- and MATE1/2-K-expressing cells were assessed in vitro. In an open-label, drug–drug interaction study, 24 healthy volunteers received a single dose of metformin 750 mg on Days 1 and 10, and a single dose of peficitinib 150 mg on Days 3 and 5–11. Blood and urine samples were collected pre-dose on Days 1 and 10, and at intervals ≤ 48 h post-dose. Metformin concentration was determined by liquid chromatography–tandem mass spectrometry and its pharmacokinetic parameters calculated. RESULTS: Peficitinib, but not H2, inhibited metformin uptake into OCT1- and MATE1/2-K-expressing cells. Repeated-dose administration of peficitinib reduced metformin area under the concentration–time curve from 0 h extrapolated to infinity (AUC(inf)) by 17.4%, maximum plasma concentration (C(max)) by 17.0%, and renal clearance (CL(R)) by 12.9%. Co-administration of peficitinib with metformin was generally well tolerated. CONCLUSION: Slight changes in AUC(inf), C(max) and CL(R) of metformin were observed when co-administered with peficitinib; however, these changes were considered not clinically relevant. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00228-020-02876-2) contains supplementary material, which is available to authorized users.