一项全面的QT研究，以评估单剂量10μg艾塞那肽对健康受试者心脏复极化的影响。
A thorough QT study to evaluate the effects of singledose exenatide 10 μg on cardiac repolarization in healthy subjects.
作者信息
Linnebjerg H, Seger M, Kothare P A, Hunt T, Wolka A M, Mitchell M I
机构信息
Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey, UK.
出版信息
Int J Clin Pharmacol Ther. 2011 Oct;49(10):594-604. doi: 10.5414/cp201462.
OBJECTIVE
This was a singledose, randomized, positive- and placebo-controlled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion.
METHODS
Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 μg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 μg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericia's correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored.
RESULTS
Based on ΔQTcF and ΔQTcI assessments, exenatide 10 μg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatide's glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (-1.5 (95% CI -2.2, -0.7), p < 0.001) and between plasma glucose and ΔQTcI (-1.6 (95% CI -2.3, -0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated.
CONCLUSION
This study demonstrated that single-dose exenatide 10 μg was not associated with clinically meaningful prolongation of the QTc interval.
目的
这是一项单剂量、随机、阳性对照和安慰剂对照、双模拟、双盲、3期交叉的全面QT研究，研究对象为艾塞那肽，一种用于治疗2型糖尿病的胰高血糖素样肽-1受体激动剂，它以葡萄糖依赖的方式增强胰岛素分泌。
方法
健康受试者（n = 70）进行了初始耐受性筛查，连续3天每天皮下注射10μg艾塞那肽。通过耐受性筛查的受试者（n = 62）接受10μg艾塞那肽、安慰剂和莫西沙星（口服400mg；阳性对照），给药间隔约为5天的洗脱期。采集12导联心电图以及用于检测血浆艾塞那肽、葡萄糖和胰岛素的血样。QT间期采用弗里德里西亚校正法（QTcF）和个体校正法（QTcI）进行心率校正，并分析其相对于给药前的变化（ΔQTcF或ΔQTcI）。还探讨了QTc间期与血浆艾塞那肽、葡萄糖和胰岛素浓度之间的关系。
结果
基于ΔQTcF和ΔQTcI评估，与安慰剂相比，10μg艾塞那肽未显示出具有临床意义的QT间期延长；两种校正方法下，与安慰剂最大平均差异的双侧90%置信区间（CI）上限均<10毫秒。血浆艾塞那肽与ΔΔQTcF之间观察到正斜率（0.02（95%CI 0.01，0.03），p<0.001）；血浆艾塞那肽浓度与ΔΔQTcI之间未观察到显著斜率（0.01（95%CI 0.00，0.02），p = 0.064）。血浆艾塞那肽与QTc的分析可能因艾塞那肽的降糖作用而混淆。血浆葡萄糖与ΔQTcF之间观察到负斜率（-1.5（95%CI -2.2，-0.7），p<0.001），血浆葡萄糖与ΔQTcI之间也观察到负斜率（-1.6（95%CI -2.3，-0.9），p<0.0001）。血浆胰岛素与ΔQTcF不相关。
结论
本研究表明，单剂量10μg艾塞那肽与QTc间期无临床意义的延长无关。
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