title: Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants.
abstract: OBJECTIVE
  Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants.
  
  
  METHODS
  All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 μg) + ethinyl estradiol (30 μg))/day (day 1), canagliflozin 200 mg/day (days 4 - 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 - 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 - 7)) in period 1, and with canagliflozin 300 mg/day (days 1 - 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 - 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 - 7 (periods 1 and 2) (study 3). Warfarin's pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2).
  
  
  RESULTS
  Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin's PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted.
  
  
  CONCLUSIONS
  Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.forename: Prasarn
authors.initials: P
authors.lastname: Manitpisitkul
authors.forename: Nicole
authors.initials: N
authors.lastname: Vaccaro
authors.forename: Apexa
authors.initials: A
authors.lastname: Bernard
authors.forename: Donna
authors.initials: D
authors.lastname: Skee
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.forename: Hong
authors.initials: H
authors.lastname: Tian
authors.forename: Sveta
authors.initials: S
authors.lastname: Weiner
authors.forename: Hans
authors.initials: H
authors.lastname: Stieltjes
authors.forename: Sue
authors.initials: S
authors.lastname: Sha
authors.forename: Paul
authors.initials: P
authors.lastname: Rothenberg
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D000068896:Canagliflozin; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005960:Glucosides / Q000008:administration & dosage* / Q000009:adverse effects; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D019934:International Normalized Ratio; D016912:Levonorgestrel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D019338:Polypharmacy; D018570:Risk Assessment; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D002316:Cardiotonic Agents; D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C072593:ethinyl estradiol, levonorgestrel drug combination; D000068896:Canagliflozin; D004997:Ethinyl Estradiol; D014859:Warfarin; D016912:Levonorgestrel; D004077:Digoxin