Dubourg Julie, Perrimond-Dauchy Sandrine, Felices Mathieu, Bolze Sébastien, Voiriot Pascal, Fouqueray Pascale
POXEL S.A., 259/261 Avenue Jean Jaurès, 69007, Lyon, France.
Phinc Development, 36 rue Victor Basch, Massy, 91300, France.
Eur J Clin Pharmacol. 2020 Oct;76(10):1393-1400. doi: 10.1007/s00228-020-02929-6. Epub 2020 Jun 18.
Imeglimin is the first in a new class of oral antidiabetic agents, the glimins, currently in development to improve glycemic control in patients with type 2 diabetes mellitus. A thorough QT study was conducted to establish electrophysiological effects of therapeutic and supratherapeutic doses of imeglimin on cardiac repolarization.
In this randomized, double-blind, four-period, placebo and active controlled crossover study, healthy subjects were administered a single dose of imeglimin 2250 mg, imeglimin 6000 mg, moxifloxacin 400 mg, and placebo. 12-Lead Holter ECGs were recorded from 1 h before dosing until at least 24 h after each dose. This study was performed at a single-center inpatient clinical pharmacology unit.
The upper bound of the two-sided 90% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTc intervals (ΔΔQTcF) did not exceed the regulatory threshold of 10 ms in any of the imeglimin dose groups. There were no QTcF values above 500 ms nor changes from pre-dose in QTcF above 60 ms in the imeglimin groups. Imeglimin did not exert a relevant effect on heart rate and PR or QRS intervals. Assay sensitivity was demonstrated by the effect of moxifloxacin 400 mg, with a lower bound two-sided 90% confidence interval for ΔΔQTcF of 10.6 ms.
This thorough QT study demonstrated that therapeutic and supratherapeutic exposures of imeglimin did not induce a QT/QTc prolongation with a strong confidence as evidenced by the assay sensitivity.
TRIAL REGISTRATION NUMBER/DATE: NCT02924337/ October 5, 2016.
依美格列明是新型口服抗糖尿病药物（格列明类）中的首个药物，目前正处于研发阶段，用于改善2型糖尿病患者的血糖控制。进行了一项全面的QT研究，以确定治疗剂量和超治疗剂量的依美格列明对心脏复极化的电生理效应。
在这项随机、双盲、四周期、安慰剂和活性对照交叉研究中，健康受试者分别接受单剂量的依美格列明2250mg、依美格列明6000mg、莫西沙星400mg和安慰剂。在给药前1小时至每次给药后至少24小时记录12导联动态心电图。本研究在单中心住院临床药理学单位进行。
在任何依美格列明剂量组中，时间匹配、安慰剂减去、基线调整后的QTc间期（ΔΔQTcF）的双侧90%置信区间上限均未超过10ms的监管阈值。依美格列明组中没有QTcF值高于500ms，也没有QTcF较给药前变化超过60ms。依美格列明对心率、PR或QRS间期没有相关影响。400mg莫西沙星的效应证明了检测的敏感性，其ΔΔQTcF的双侧90%置信区间下限为10.6ms。
这项全面的QT研究表明，依美格列明的治疗暴露和超治疗暴露不会导致QT/QTc延长，检测敏感性证明了这一点。
试验注册号/日期：NCT02924337/2016年10月5日。
