Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus

This study characterized single- and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG], urinary glucose excretion [UGE024h], and 24-hour mean plasma glucose [MPG024h]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (Cmax) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which Cmax was observed were dose-independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady-state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose- and exposure-dependent. All canagliflozin doses decreased RTG, increased UGE024h, and reduced MPG024h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG024h ranged from 4257mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment-related serious AEs, AE-related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once-daily dosing regimen.