Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus
Pharmacokinetics and Pharmacodynamics of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, in Subjects With Type 2 Diabetes Mellitus
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DOI：
10.1002/jcph.88
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发表时间：
2013-06-01
影响因子：
2.9
通讯作者：
Rothenberg, Paul L.
中科院分区：
文献类型：
--
作者：
Devineni, Damayanthi;Curtin, Christopher R.;Rothenberg, Paul L.
本研究描述了2型糖尿病受试者中卡格列净及其O-葡糖苷酸代谢产物（M5和M7）单次和多次给药的药代动力学以及卡格列净的药效学（葡萄糖肾阈值[RTG]、尿糖排泄[UGE 024 h]和24小时平均血糖[MPG 024 h]）。36例随机化受试者接受卡格列净50、100或300 mg/天或安慰剂治疗7天。第1天和第7天，Canagliflozin及其代谢产物的血药浓度-时间曲线下面积和最大血药浓度（Cmax）呈剂量依赖性增加。半衰期和观察到Cmax的时间与剂量无关。全身磨牙M5暴露量是卡格列净的一半; M7暴露量与卡格列净相似。在所有活性治疗组中，卡格列净血浆浓度在第4天达到稳态。药效学效应具有剂量和剂量依赖性。在第1天和第7天，与安慰剂相比，所有卡格列净剂量均降低RTG，增加UGE 024 h，降低MPG 024 h。第7天，卡格列净治疗组MPG 024 h的减去安慰剂的最小二乘平均降低范围为4257 mg/dL。两种治疗之间的不良事件（AE）平衡;未发生治疗相关严重AE、AE相关停药或常规安全性评价中有临床意义的不良变化。在2型糖尿病受试者中观察到的卡格列净药代动力学/药效学特征支持每日一次给药方案。
This study characterized single- and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG], urinary glucose excretion [UGE024h], and 24-hour mean plasma glucose [MPG024h]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (Cmax) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which Cmax 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 RTG, increased UGE024h, and reduced MPG024h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG024h ranged from 4257mg/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.