Wang Yitong, Xu Bingfeng, Zhu Lixia, Lou Kun, Chen Yingli, Zhao Xia, Wang Qian, Xu Ling, Guo Xiaohui, Ji Linong, Cui Yimin, Fang Yi
Department of Pharmacy, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical, Peking University, Beijing, 100191, China.
Clin Drug Investig. 2017 Dec;37(12):1107-1115. doi: 10.1007/s40261-017-0569-1.
Recombinant glucagon-like peptide-1 receptor agonist (rE-4) is a glucagon-like peptide-1 receptor agonist, which has the same amino acid sequence to exenatide, except for the C-terminal deamidated. This study assessed the pharmacokinetics and preliminary pharmacodynamics of rE-4, following single and multiple subcutaneous injections in Chinese patients with type 2 diabetes mellitus (T2DM).
In the randomized, open-label study, Chinese patients with T2DM (n = 36) were randomly assigned to three groups of rE-4 (n = 12), rE-4 with metformin (n = 12) and exenatide (n = 12, as the control group) for 12 weeks. rE-4 and exenatide were administered by subcutaneous injection in the abdomen, and metformin was given by oral administration. Patients received rE-4 or exenatide 5 μg twice a day for the first 4 weeks and adjusted the dose of rE-4 or exenatide to 10 μg twice a day at day 29 for the following 8 weeks, if their glycated albumin (GA) values were still greater than 17%. We evaluated pharmacokinetic parameters of rE-4 and exenatide, fasting plasma glucose (FPG), 2-h postprandial blood glucose (PG2 h), glycosylated hemoglobin (HbA1c) and body weight at designated time points.
Thirty-six patients were enrolled, and 29 subjects finished the study. rE-4 was absorbed quickly with a median peak-reaching time (t ) of 0.8-1.5 h and eliminated rapidly with a median terminal half-life (t ) of 1.6-1.9 h. The exposure of rE-4 increased in an approximately dose-proportional method without accumulation. rE-4 10 μg twice a day could reduce FPG (2.29 mmol/L), PG2 h (6.00 mmol/L), HbA1c (1.19%) and body weight (0.48 kg) from baseline to 12 weeks, with no statistical significance compared with exenatide (FPG: ~1.88 mmol/L; PG2 h: ~6.66 mmol/L; HbA1c: ~1.13%; body weight: ~0.47 kg) and rE-4 with metformin (FPG: ~2.33 mmol/L; PG2 h: ~6.51 mmol/L; HbA1c: ~0.84%; body weight: ~1.16 kg) (p > 0.05).
rE-4 twice a day has a pharmacokinetic profile similar to exenatide and rE-4 with metformin after single and multiple doses in Chinese patients with T2DM. Also, rE-4 could improve glycemic control effectively. CLINICALTRIALS.
NCT01342042.
重组胰高血糖素样肽-1受体激动剂（rE-4）是一种胰高血糖素样肽-1受体激动剂，除C末端脱酰胺外，其氨基酸序列与艾塞那肽相同。本研究评估了rE-4在中国2型糖尿病（T2DM）患者单次和多次皮下注射后的药代动力学和初步药效学。
在这项随机、开放标签研究中，中国T2DM患者（n = 36）被随机分为三组，分别接受rE-4（n = 12）、rE-4联合二甲双胍（n = 12）和艾塞那肽（n = 12，作为对照组）治疗12周。rE-4和艾塞那肽通过腹部皮下注射给药，二甲双胍通过口服给药。患者在最初4周每天两次皮下注射rE-4或艾塞那肽5 μg，如果糖化白蛋白（GA）值仍大于17%，则在第29天将rE-4或艾塞那肽剂量调整为每天两次10 μg，持续接下来的8周。我们在指定时间点评估了rE-4和艾塞那肽的药代动力学参数、空腹血糖（FPG）、餐后2小时血糖（PG2 h）、糖化血红蛋白（HbA1c）和体重。
36例患者入组，29例受试者完成研究。rE-4吸收迅速，中位达峰时间（t ）为0.8 - 1.5小时，消除迅速，中位末端半衰期（t ）为1.6 - 1.9小时。rE-4的暴露量以近似剂量比例的方式增加，无蓄积。每天两次10 μg的rE-4可使FPG（约2.29 mmol/L）、PG2 h（约6.00 mmol/L）、HbA1c（约1.19%）和体重（约0.48 kg）从基线降至12周，与艾塞那肽（FPG：约1.88 mmol/L；PG2 h：约6.66 mmol/L；HbA1c：约1.13%；体重：约0.47 kg）和rE-4联合二甲双胍（FPG：约2.33 mmol/L；PG2 h：约6.51 mmol/L；HbA1c：约0.84%；体重：约1.16 kg）相比，差异无统计学意义（p > 0.05）。
在中国T2DM患者中，每天两次的rE-4在单次和多次给药后的药代动力学特征与艾塞那肽以及rE-4联合二甲双胍相似。此外，rE-4可有效改善血糖控制。临床试验。
NCT01342042。
