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


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


BACKGROUND
Mitsubishi Tanabe Pharma Corporation.


BACKGROUND
ClinicalTrials.gov#NCT00707954.
Medical Affairs Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. Iijima.Hiroaki@mm.mt-pharma.co.jp.
Hiroaki
H
Iijima
Development Division, Clinical Pharmacology Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Takayuki
T
Kifuji
Development Division, Clinical Research Department II, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
Nobuko
N
Maruyama
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nobuya
N
Inagaki
D000328:Adult; D000368:Aged; D044466:Asian People; D001786:Blood Glucose / Q000032:analysis; D000068896:Canagliflozin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin
Canagliflozin; Dehydration; Japanese patients; Pharmacodynamics; Pharmacokinetics; Sodium glucose co-transporter 2 inhibitor; Type 2 diabetes mellitus; Urine volume