title: Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.forename: Nicole
authors.initials: N
authors.lastname: Vaccaro
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.forename: Hans
authors.initials: H
authors.lastname: Stieltjes
authors.forename: Ewa
authors.initials: E
authors.lastname: Wajs
mesh_terms: D000328:Adult; D000068896:Canagliflozin; D004305:Dose-Response Relationship, Drug; D005260:Female; D005960:Glucosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin