Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects
Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects
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DOI：
10.1055/s-0043-104779
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发表时间：
2017-06-01
期刊：
影响因子：
2.2
通讯作者：
Ikeda, Sachiya
中科院分区：
文献类型：
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作者：
Kasahara-Ito, Nahoko;Fukase, Hiroyuki;Ikeda, Sachiya
目的 Tofogliflozin 是一种选择性口服钠-葡萄糖协同转运蛋白 2 抑制剂，用于治疗 2 型糖尿病。在健康男性受试者中研究了托格列净的药代动力学、药效学和安全性。方法进行了三项研究：56 名日本受试者和 24 名白人受试者的单次递增剂量研究（10-640 mg）；在 24 名日本受试者中进行的多剂量递增研究（2.5-80 毫克，每日一次，持续 7 天）；以及对 30 名日本受试者的食物效应研究（20-40 mg）。结果 Tofogliflozin 被迅速吸收并从体循环中消除，t(1/2) 为 5-6 小时。暴露剂量成比例增加至 320 mg。日本人和白人受试者的体重校正暴露相似。托格列净的尿排泄量为剂量的 17.1% 至 27.4%。每天给药一次托格列净不会蓄积。食物摄入使 C-max 降低约 30%，但未改变 AUC(0-int)。托格列净引起剂量依赖性每日尿葡萄糖排泄(UGE(0-24h))，但给药时的食物摄入条件对其没有影响。托格列净血浆平均浓度(C-avg)与UGE(0-24h)之间的暴露-反应关系与E-max模型拟合良好。没有导致停药或低血糖发作的严重不良事件。结论 托格列净单次和多次给药通常耐受性良好。托福格列净的暴露量与剂量成比例，最高可达 320 mg，且每日一次多次给药不会累积。该模型表明，对应于 20 至 40 mg 剂量的 C-avg 超过 100 ng/mL，托福格列净的效果几乎达到最大。
Purpose Tofogliflozin is a selective oral inhibitor of sodium-glucose cotransporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects.Methods Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects.Results Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t(1/2) of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4 % of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased C-max by approximately 30 % but did not change AUC(0-int). Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE(0-24h)), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (C-avg) and UGE(0-24h) fitted E-max model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia.Conclusions Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL C-avg corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin.