Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus

Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved worldwide for the treatment of patients with type 2 diabetes mellitus (T2DM). The present study evaluated pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with T2DM. Canagliflozin, at doses of 25, 100, 200, or 400 mg, was administered as a single dose and, after a washout of 1 day, in repeated doses for 14 consecutive days to 61 subjects in a randomized, double-blind, placebo-controlled study. Plasma concentrations of canagliflozin and urinary glucose excretion (UGE) were measured, and renal threshold for glucose excretion (RTG) was calculated. Safety was evaluated on the basis of adverse event (AE) reports, blood and urine laboratory parameters, and vital signs. Plasma canagliflozin maximum concentration and area under the concentration-time curve (AUC) values increased in a dose-dependent manner with the time to maximum concentration (t (max)) of 1.0 h and elimination half-life (t (1/2)) of 10.22-13.26 h on Day 1. No significant changes in t (max) and t (1/2) were observed after multiple-dose administration. The linearity factors, as calculated from the ratios of AUC(0-24h) on Day 16 to AUC(0-a) on Day 1, were close to 1 in all canagliflozin groups. Canagliflozin increased UGE(0-24h) (80-110 g/day with canagliflozin a parts per thousand yen100 mg) and decreased RTG from the first day of treatment; these effects were sustained during the entire period of multiple administration. No significant AEs were noted. Urine volume was slightly increased on Day 1, but subsequent changes after repeated doses for 14 days were small. Urinary sodium tended to be higher in the early treatment period, whereas no particular change was observed in serum osmolality and hematocrit. Canagliflozin increased UGE, decreased RTG, and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM. Mitsubishi Tanabe Pharma Corporation. ClinicalTrials.gov#NCT00707954.