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

Abstract

Introduction: 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.

Methods: 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.

Results: 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 AUC0-24h on Day 16 to AUC0-∞ on Day 1, were close to 1 in all canagliflozin groups. Canagliflozin increased UGE0-24h (80-110 g/day with canagliflozin ≥100 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.

Conclusion: Canagliflozin increased UGE, decreased RTG, and was well tolerated throughout the entire period of multiple administrations in Japanese patients with T2DM.

Funding: Mitsubishi Tanabe Pharma Corporation.

Trial registration: ClinicalTrials.gov#NCT00707954.

Keywords: Canagliflozin; Dehydration; Japanese patients; Pharmacodynamics; Pharmacokinetics; Sodium glucose co-transporter 2 inhibitor; Type 2 diabetes mellitus; Urine volume.

Figures

Fig. 1

Study design (a) and participant flow (b)

Fig. 2

Plasma concentration–time profiles after canagliflozin treatment on Days 1 and 16. Data are presented as the mean ± standard deviation

Fig. 3

Effect of canagliflozin on changes in 24-h UGE (a) and 24-h mean RTG (b). Data are mean ± standard deviation. UGE urinary glucose excretion, RTG renal threshold for glucose

Fig. 4

Effects of canagliflozin on the changes from baseline in urinary volume (a), water intake (b), and urinary sodium excretion (c). Data are mean ± standard deviation

Fig. 5

Change from baseline on Day 1 in urine volume (a), sodium excretion (b), and urine osmolality (c). Data are mean ± standard deviation

Fig. 6

Effects of canagliflozin on serum osmolality (a) and hematocrit (b). Data are mean ± standard deviation