Department of Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, Switzerland.
Department of Safety Science, Roche Translational Clinical Research Center, Inc., New York, New York.
Diabetes Obes Metab. 2017 Oct;19(10):1446-1453. doi: 10.1111/dom.13025. Epub 2017 Jul 25.
To evaluate the pharmacodynamics, pharmacokinetics and safety of single subcutaneous (s.c.) injection of ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in healthy subjects.
A total of 51 healthy volunteers were enrolled in this double-blind, placebo-controlled study investigating RG7697 doses ranging from 0.03 to 5 mg. Adverse events (AEs) were monitored and drug concentrations, fasting glycaemic variables, vital signs, ECG, antibody formation and routine laboratory variables were assessed. A meal tolerance test (MTT) was performed at the same time on day -1 (baseline) and day 1.
RG7697 was generally well tolerated in healthy participants after s.c. injections up to 3.6 mg. Tolerability was limited by gastrointestinal AEs (nausea and vomiting) at the highest dose. There was a small dose-dependent increase in heart rate. No episodes of hypoglycaemia occurred. RG7697 concentrations peaked at 2 to 4 hours post-dose with a half-life of 19 to 25 hours. During MTT, RG7697 at doses ≥1.8 mg, reduced glucose maximum plasma concentration (C ; -46%) without affecting overall glucose area under the curve (AUC). Its effect on insulin was more pronounced, with reductions in both C (-64%) and AUC (-51%). Pharmacodynamic variables were well correlated to RG7697 average plasma concentration during MTT, with IC (average concentration required for 50% reduction) values of 49 and 24.5 ng/mL for glucose and insulin, respectively.
Single s.c. injections of RG7697 up to 3.6 mg were generally well tolerated. Evidence of glycaemic effect and pharmacokinetic profiles consistent with once-daily dosing render this drug candidate suitable to be further tested in multiple-dose clinical trials in patients with type 2 diabetes.
评估新型双重葡萄糖依赖性胰岛素促泌多肽/胰高血糖素样肽-1 激动剂 RG7697 单剂皮下递增给药在健康受试者中的药效学、药代动力学和安全性。
本双盲、安慰剂对照研究共纳入 51 名健康志愿者，考察了 RG7697 剂量范围为 0.03 至 5mg。监测不良事件（AE），评估药物浓度、空腹血糖变量、生命体征、心电图、抗体形成和常规实验室变量。在第-1 天（基线）和第 1 天同时进行了口服葡萄糖耐量试验（OGTT）。
在健康受试者中，RG7697 经皮下注射剂量高达 3.6mg 时通常具有良好的耐受性。在最高剂量时，耐受性受到胃肠道 AE（恶心和呕吐）的限制。心率有轻微的剂量依赖性增加。未发生低血糖事件。RG7697 浓度在给药后 2 至 4 小时达到峰值，半衰期为 19 至 25 小时。在 OGTT 期间，剂量≥1.8mg 的 RG7697 降低了葡萄糖最大血浆浓度（C；-46%），而不影响葡萄糖 AUC。其对胰岛素的作用更为明显，C（-64%）和 AUC（-51%）均降低。在 OGTT 期间，药效学变量与 RG7697 平均血浆浓度相关性良好，葡萄糖和胰岛素的 IC（使 50%降低所需的平均浓度）值分别为 49 和 24.5ng/mL。
单剂皮下注射 RG7697 高达 3.6mg 时通常具有良好的耐受性。血糖效应和药代动力学特征的证据与每日一次给药一致，这使得该候选药物适合在 2 型糖尿病患者的多剂量临床试验中进一步测试。
