Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants

Int J Clin Pharmacol Ther. 2015 Feb;53(2):129-38. doi: 10.5414/CP202218.


Objective: To evaluate the pharmacokinetics of oral canagliflozin and its O-glucuronide metabolites (M7 and M5) after single and multiple doses in healthy adult participants. The pharmacodynamics, safety, and tolerability of canagliflozin were also evaluated.

Methods: In this open-label, single- (day 1) and multiple-dose (days 4-9), parallel-group, phase 1 study, 27 healthy participants were randomized into three groups (1:1:1) to receive 50, 100, or 300 mg canagliflozin. Pharmacokinetics and pharmacodynamics were assessed at pre-pecified timepoints on days 1, 9, and 10.

Results: Mean area under the plasma concentration-time curve, and the maximum observed plasma concentration of canagliflozin, M7, and M5 increased in a dose-dependent manner, across all the 3 doses, following single- and multiple-dose administration. The mean apparent elimination half-lives of canagliflozin, M7, and M5 were independent of the dose. Canagliflozin decreased the renal threshold for glucose (RTG) and increased the urinary glucose excretion (UGE) in a concentration- and dose-dependent manner. The relationship between drug concentrations and RTG was described by a sigmoidal relationship with RTGmin (minimum value of RTG) of 37.5 ng/mL (95% confidence interval (CI): 34.3, 40.8) and half-maximal effective concentration (EC50) of 21 ng/mL (95% CI: 18.3, 23.8). No deaths, serious adverse events, hypoglycemic events, or discontinuations due to adverse events were observed.

Conclusion: Pharmacokinetics of canagliflozin and its metabolites (M7 and M5) were linear, and no time-dependent changes were observed after single- and multiple-dose administration. Similarly, pharmacodynamic effects of canagliflozin on RTG and UGE were found to be dose- and concentration-dependent. Overall, canagliflozin was well-tolerated in healthy participants.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Canagliflozin
  • Dose-Response Relationship, Drug
  • Female
  • Glucosides / administration & dosage
  • Glucosides / adverse effects
  • Glucosides / pharmacokinetics*
  • Glucosides / pharmacology*
  • Humans
  • Male
  • Middle Aged
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Thiophenes / administration & dosage
  • Thiophenes / adverse effects
  • Thiophenes / pharmacokinetics*
  • Thiophenes / pharmacology*


  • Glucosides
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiophenes
  • Canagliflozin