Effect of canagliflozin on the pharmacokinetics of glyburide, metformin, and simvastatin in healthy participants

Clin Pharmacol Drug Dev. May-Jun 2015;4(3):226-36. doi: 10.1002/cpdd.166. Epub 2014 Oct 27.

Abstract

Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase-1 studies in healthy participants. In these open-label, fixed sequence studies, participants received: Study 1-glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4-8), canagliflozin with glyburide (Day 9); Study 2-metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4-7), metformin with canagliflozin (Day 8); Study 3-simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2-6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co-administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUC]) of glyburide and its metabolites (4-trans-hydroxy-glyburide and 3-cis-hydroxy-glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though Cmax and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug-drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well-tolerated in healthy participants.

Trial registration: ClinicalTrials.gov NCT01733108 NCT01273571 NCT01821027.

Keywords: canagliflozin; glyburide; metformin; pharmacokinetics; simvastatin; type-2 diabetes mellitus.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Area Under Curve
  • Argentina
  • Biological Availability
  • Biotransformation
  • Canagliflozin / administration & dosage*
  • Canagliflozin / adverse effects
  • Drug Administration Schedule
  • Drug Interactions
  • Female
  • Glyburide / administration & dosage
  • Glyburide / adverse effects
  • Glyburide / blood
  • Glyburide / pharmacokinetics*
  • Half-Life
  • Healthy Volunteers
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / blood
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Male
  • Metabolic Clearance Rate
  • Metformin / administration & dosage
  • Metformin / adverse effects
  • Metformin / blood
  • Metformin / pharmacokinetics*
  • Middle Aged
  • Models, Biological
  • Simvastatin / administration & dosage
  • Simvastatin / adverse effects
  • Simvastatin / blood
  • Simvastatin / pharmacokinetics*
  • United States
  • Young Adult

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypoglycemic Agents
  • Canagliflozin
  • Metformin
  • Simvastatin
  • Glyburide

Associated data

  • ClinicalTrials.gov/NCT01733108
  • ClinicalTrials.gov/NCT01273571
  • ClinicalTrials.gov/NCT01821027