Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus.
Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus.
复制标题
DOI：
10.1007/s12325-015-0234-0
复制
发表时间：
2015-08
影响因子：
3.8
通讯作者：
Inagaki N
中科院分区：
文献类型：
--
作者：
Iijima H;Kifuji T;Maruyama N;Inagaki N
Canagliflozin是一种钠葡萄糖共转运蛋白2抑制剂，在全球范围内被批准用于治疗2型糖尿病（T2DM）患者。本研究评估了卡格列净在日本T2DM患者中的药代动力学、药效学和安全性。在一项随机、双盲、安慰剂对照研究中，加格列净以25、100、200或400 mg的剂量作为单剂量给药，在1天洗脱期后，对61名受试者连续14天重复给药。测定卡格列净血药浓度和尿糖排泄量（UGE），计算葡萄糖排泄肾阈值（RTG）。安全性评估基于不良事件（AE）报告、血液和尿液实验室参数以及生命体征。血浆canagliflozin最高浓度和浓度-时间曲线下面积（AUC）值呈剂量依赖性增加，第1天达到最高浓度的时间（t max）为1.0 h，消除半衰期（t 1/2）为10.22-13.26 h。多次给药后tmax和t1 /2无明显变化。从第16天的AUC0 - 24h与第1天的AUC0 -∞之比计算，所有卡格列净组的线性因子都接近于1。从治疗第一天起，卡格列净使UGE0-24h升高（80-110 g/天，卡格列净≥100 mg）， RTG降低；这些效果在整个多次给药期间持续存在。未见明显ae。第1天尿量略有增加，但重复给药后14天的变化很小。尿钠倾向于在治疗早期较高，而血清渗透压和红细胞压积没有特别的变化。在日本T2DM患者中，卡格列净增加了UGE，降低了RTG，并且在整个多次给药期间耐受性良好。三菱田边制药公司。ClinicalTrials.gov # NCT00707954。本文的在线版本（doi:10.1007/s12325-015-0234-0）包含补充资料，仅供授权用户使用。
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 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. 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. The online version of this article (doi:10.1007/s12325-015-0234-0) contains supplementary material, which is available to authorized users.