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Evaluation of the potential interaction between tofacitinib and drugs that undergo renal tubular secretion using metformin, an in vivo marker of renal organic cation transporter 2
Author(s) -
Klamerus Karen J.,
Alvey Christine,
Li Lei,
Feng Bo,
Wang Rong,
Kaplan Irina,
Shi Haihong,
Dowty Martin E.,
Krishnaswami Sriram
Publication year - 2014
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.120
Subject(s) - tofacitinib , medicine , pharmacokinetics , pharmacology , metformin , organic cation transport proteins , cmax , janus kinase inhibitor , urology , gastroenterology , transporter , chemistry , rheumatoid arthritis , biochemistry , insulin , gene
Abstract Tofacitinib is a novel, oral Janus kinase inhibitor. The potential for drug–drug interactions (DDIs) between tofacitinib and drugs that undergo renal tubular secretion was evaluated using metformin as a probe transporter substrate, and genotyping for organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion 1 polymorphisms. Twenty‐four healthy male subjects completed this open‐label, fixed‐sequence study. Subjects were administered a single oral metformin 500 mg dose on Days 1 and 4, and multiple oral tofacitinib 30 mg twice daily doses on Days 2, 3, and 4. Subjects underwent serial blood and urine samplings (Days 1 and 4) to estimate metformin pharmacokinetics. A single blood sample for tofacitinib was collected 2 hours after the morning dose (Day 4). The 90% confidence intervals for the ratios of maximum plasma concentration, area under the curve and renal clearance of metformin, with and without tofacitinib, were contained within the 80–125% acceptance range commonly used to establish a lack of DDI. No deaths, serious adverse events (AEs), severe AEs or discontinuations due to AEs were reported. The study confirms tofacitinib is unlikely to impact the pharmacokinetics of drugs that undergo renal tubular secretion, and concurs with its weak in vitro OCT2 inhibitory profile.