A drug\u2013drug interaction study to evaluate the impact of peficitinib on OCT1- and MATE1-mediated transport of metformin in healthy volunteers

Mai Shibata,Junko Toyoshima,Yuichiro Kaneko,Tetsuya Nishimura,Kazuo Oda

doi:10.1007/s00228-020-02876-2

Mai Shibata, Junko Toyoshima + Show 3 more

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https://doi.org/10.1007/s00228-020-02876-2

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Abstract

PurposePeficitinib 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.MethodsInhibitory 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.ResultsPeficitinib, 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 (AUCinf) by 17.4%, maximum plasma concentration (Cmax) by 17.0%, and renal clearance (CLR) by 12.9%. Co-administration of peficitinib with metformin was generally well tolerated.ConclusionSlight changes in AUCinf, Cmax and CLR of metformin were observed when co-administered with peficitinib; however, these changes were considered not clinically relevant.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease that is associated with chronic, painful joint inflammation [1, 2]
We investigated the effects of peficitinib and H2, which has the highest exposure of the three metabolites [15], on the uptake of metformin into human organic cation transporter 1 (OCT1)/2- and multidrug and toxin extrusion 1 (MATE1)/2-Kexpressing cells
Uptake of [14C]metformin into OCT1, OCT2, MATE1- and MATE2K-expressing cells in the presence of these inhibitors was reduced to 4.7–6.9%, 10.5–12.2%, 11.9–14.7% and 8.2–15.1%, respectively, of uptake in the absence of inhibitors

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease that is associated with chronic, painful joint inflammation [1, 2]. Based on the assumption that peficitinib is stable in the gastrointestinal tract, a clinical mass balance study of six healthy male subjects administered with a single oral dose of 14C-labelled peficitinib ([14C]peficitinib) suggested that approximately 64% of the peficitinib dose was absorbed [15]. This was based on mean recovery of peficitinib in urine and faeces of 36.8% and 56.6%, respectively, and mean faecal excretion of 29.8% of the administered dose as unchanged peficitinib [15]

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