title: 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.
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.
authors.affiliation: Pfizer Inc, San Diego, CA, USA.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Klamerus
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Alvey
authors.affiliation: Pfizer Inc, San Diego, CA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Pfizer Inc, San Diego, CA, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kaplan
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Pfizer Inc, Andover, MA, USA.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dowty
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001530:Belgium; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D064368:Healthy Volunteers; D006801:Humans; D000075242:Janus Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008875:Middle Aged; D000075102:Organic Cation Transporter 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage* / Q000097:blood; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood; D011758:Pyrroles / Q000008:administration & dosage* / Q000097:blood; D065667:Renal Elimination; D014162:Transfection; D055815:Young Adult
chemical_list: D000075242:Janus Kinase Inhibitors; D000075102:Organic Cation Transporter 2; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C491013:SLC22A2 protein, human; C479163:tofacitinib; D008687:Metformin
keywords: drug-drug interactions; metformin; organic cation transporter; tofacitinib; tubular secretion