1. Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants.
- Author
-
Devineni D, Manitpisitkul P, Vaccaro N, Bernard A, Skee D, Mamidi RN, Tian H, Weiner S, Stieltjes H, Sha S, and Rothenberg P
- Subjects
- Adult, Anticoagulants administration & dosage, Anticoagulants blood, Area Under Curve, Blood Coagulation drug effects, Canagliflozin, Cardiotonic Agents administration & dosage, Cardiotonic Agents blood, Contraceptives, Oral, Combined administration & dosage, Contraceptives, Oral, Combined blood, Cross-Over Studies, Digoxin administration & dosage, Digoxin blood, Drug Administration Schedule, Drug Combinations, Drug Dosage Calculations, Drug Interactions, Ethinyl Estradiol administration & dosage, Ethinyl Estradiol blood, Female, Glucosides adverse effects, Half-Life, Healthy Volunteers, Humans, Hypoglycemic Agents adverse effects, International Normalized Ratio, Levonorgestrel administration & dosage, Levonorgestrel blood, Male, Metabolic Clearance Rate, Middle Aged, Polypharmacy, Risk Assessment, Sodium-Glucose Transporter 2 metabolism, Thiophenes adverse effects, Warfarin administration & dosage, Warfarin blood, Young Adult, Anticoagulants pharmacokinetics, Cardiotonic Agents pharmacokinetics, Contraceptives, Oral, Combined pharmacokinetics, Digoxin pharmacokinetics, Ethinyl Estradiol pharmacokinetics, Glucosides administration & dosage, Hypoglycemic Agents administration & dosage, Levonorgestrel pharmacokinetics, Sodium-Glucose Transporter 2 Inhibitors, Thiophenes administration & dosage, Warfarin pharmacokinetics
- 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., Conclusion: Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.
- Published
- 2015
- Full Text
- View/download PDF