Takeda Global Research & Development Center, Inc., Deerfield, Illinois, USA.
Clin Pharmacol Ther. 2012 Jul;92(1):29-39. doi: 10.1038/clpt.2012.43. Epub 2012 Jun 6.
G-protein-coupled receptor 40 (GPR40), highly expressed in pancreatic β-cells, mediates free fatty acid (FFA)-induced insulin secretion. This phase I, double-blind, randomized study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel, glucose-lowering GPR40 agonist, TAK-875 (q.d., orally × 14 days), in type 2 diabetics (placebo, n = 14; at 25, 50, 100, 200, or 400 mg, n = 45). Approximately dose-proportional increases in AUC(0-24) and C(max) occurred. TAK-875 showed good tolerability with no dose-limiting side effects. Two subjects (on TAK-875) had mild hypoglycemia, probably related to prolonged fasting after oral glucose tolerance tests (OGTTs). TAK-875 showed reductions from baseline in fasting (2 to -93 mg/dl) and post-OGTT glucose (26 to -172 mg/dl), with an apparent dose-dependent increase in post-OGTT C-peptide over 14 days. Consistent with preclinical data, TAK-875 apparently acts as a glucose-dependent insulinotropic agent with low hypoglycemic risk. Its PK is suitable for once-daily oral administration.
G 蛋白偶联受体 40（GPR40）在胰腺β细胞中高度表达，介导游离脂肪酸（FFA）诱导的胰岛素分泌。这项 I 期、双盲、随机研究调查了新型降血糖 GPR40 激动剂 TAK-875（qd，口服×14 天）在 2 型糖尿病患者中的安全性、耐受性、药代动力学（PK）和药效学（PD），（安慰剂，n=14；25、50、100、200 或 400mg，n=45）。AUC（0-24）和 Cmax 呈近似剂量比例增加。TAK-875 具有良好的耐受性，无剂量限制的副作用。两名受试者（TAK-875 组）出现轻度低血糖，可能与口服葡萄糖耐量试验（OGTT）后禁食时间延长有关。TAK-875 显示空腹（2 至-93mg/dl）和 OGTT 后血糖（26 至-172mg/dl）从基线降低，14 天内 OGTT 后 C 肽呈明显剂量依赖性增加。与临床前数据一致，TAK-875 显然作为一种葡萄糖依赖性胰岛素促分泌剂，低血糖风险低。其 PK 适合每日口服一次给药。
