Tiessen R G, Castaigne J P, Dreyfus J F, Nemansky M, Kruizinga H H, van Vliet A A
1PRA International, Zuidlaren, The Netherlands.
Int J Clin Pharmacol Ther. 2008 Sep;46(9):443-52. doi: 10.5414/cpp46443.
The safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of single rising doses of a novel GLP-1 analog, CJC-1131, was evaluated.
CJC-1131 was subcutaneously injected in 8 groups (1.5 - 20.5 microg/kg) of healthy subjects (each group of six subjects included 1 placebo per dose level). CJC-1131 was also injected subcutaneously in 6 groups (1.5 - 12 microg/kg) of Type 2 diabetic patients after a 9-day washout period from their own anti-diabetic medication. Each group of 8 patients included 2 placebo-treated patients. Seven blood glucose measurements were taken daily, and meal tolerance tests were performed on the day before dosing and on Day 3.
CJC-1131 was quickly absorbed from the subcutaneous space, and a less than dose-proportional increase was found in Cmax. The half-life of CJC-1131 varied from 8.9 - 14.7 days in healthy subjects and from 9.1 - 13.8 days in patients. The maximum tolerated dose in healthy subjects was established at 12 microg/kg with nausea and vomiting being the dose-limiting events. These events occurred generally in the morning after dosing. Blood glucose levels in patients decreased on Day 1 in proportion with dose, with a maximum average decrease of 4.1 mmol/l in the highest dose group. Higher doses appeared to be related to a slight weight loss in patients.
Conjugation to albumin led to a major prolongation of the half-life of GLP-1. The tolerability of this potential antidiabetic drug seems to be limited only by gastrointestinal complaints.
评估新型胰高血糖素样肽-1（GLP-1）类似物CJC-1131单次递增剂量给药后的安全性、耐受性、药代动力学及初步药效学。
将CJC-1131皮下注射于8组（剂量为1.5 - 20.5微克/千克）健康受试者（每组6名受试者，每个剂量水平含1名安慰剂对照）。在2型糖尿病患者停用自身抗糖尿病药物9天后，将CJC-1131也皮下注射于6组（剂量为1.5 - 12微克/千克）患者。每组8名患者，其中2名接受安慰剂治疗。每天进行7次血糖测量，并在给药前一天和第3天进行餐耐量试验。
CJC-1131从皮下迅速吸收，Cmax呈小于剂量比例的增加。CJC-1131在健康受试者中的半衰期为8.9 - 14.7天，在患者中为9.1 - 13.8天。健康受试者的最大耐受剂量确定为12微克/千克，恶心和呕吐为剂量限制性事件。这些事件通常发生在给药后的早晨。患者的血糖水平在第1天随剂量成比例下降，最高剂量组平均最大降幅为4.1毫摩尔/升。较高剂量似乎与患者体重略有减轻有关。
与白蛋白结合导致GLP-1半衰期显著延长。这种潜在抗糖尿病药物的耐受性似乎仅受胃肠道不适的限制。
