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 [RT G ], urinary glucose excretion [UGE 0–24h ], and 24‐hour mean plasma glucose [MPG 0–24h ]) of canagliflozin in subjects with type 2 diabetes. Thirty‐six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration‐time curve and maximum observed plasma concentration (C max ) for canagliflozin and its metabolites increased dose‐dependently. Half‐life and time at which C max 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 RT G , increased UGE 0–24h , and reduced MPG 0–24h versus placebo on Days 1 and 7. On Day 7, placebo‐subtracted least‐squares mean decreases in MPG 0–24h ranged from 42–57 mg/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.