title: Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.
abstract: OBJECTIVE
  Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants.
  
  
  METHODS
  Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4-12); study 2: canagliflozin 300 mg (days 1-17), probenecid 500 mg twice daily (days 15-17); and study 3: canagliflozin 300 mg (days 1-8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2-8 (study 3).
  
  
  RESULTS
  Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax.
  
  
  CONCLUSIONS
  Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.forename: Nicole
authors.initials: N
authors.lastname: Vaccaro
authors.forename: Joe
authors.initials: J
authors.lastname: Murphy
authors.forename: Christopher
authors.initials: C
authors.lastname: Curtin
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.forename: Sveta
authors.initials: S
authors.lastname: Weiner
authors.forename: Shean-Sheng
authors.initials: SS
authors.lastname: Wang
authors.forename: Jay
authors.initials: J
authors.lastname: Ariyawansa
authors.forename: Hans
authors.initials: H
authors.lastname: Stieltjes
authors.forename: Ewa
authors.initials: E
authors.lastname: Wajs
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Di Prospero
authors.forename: Paul
authors.initials: P
authors.lastname: Rothenberg
mesh_terms: D000328:Adult; D000068896:Canagliflozin; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005960:Glucosides / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D011339:Probenecid / Q000009:adverse effects / Q000494:pharmacology*; D012293:Rifampin / Q000009:adverse effects / Q000494:pharmacology*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin; D016572:Cyclosporine; D011339:Probenecid; D012293:Rifampin