Absence of QTc prolongation in a thorough QT study with imeglimin, a first in class oral agent for type 2 diabetes melli
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PHARMACODYNAMICS
Absence of QTc prolongation in a thorough QT study with imeglimin, a first in class oral agent for type 2 diabetes mellitus Julie Dubourg 1 & Sandrine Perrimond-Dauchy 1 & Mathieu Felices 2 & Sébastien Bolze 1 & Pascal Voiriot 3 & Pascale Fouqueray 1 Received: 7 April 2020 / Accepted: 2 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose 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. Methods 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. Results 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. Conclusion 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 Keywords Imeglimin . QT interval . Thorough QT study . Type 2 diabetes mellitus
Introduction * Julie Dubourg [email protected] Sandrine Perrimond-Dauchy [email protected] Mathieu Felices [email protected] Sébastien Bolze [email protected] Pascal Voiriot [email protected] Pascale Fouqueray [email protected] 1
POXEL S.A., 259/261 Avenue Jean Jaurès, 69007 Lyon, France
2
Phinc Development, 36 rue Victor Basch, Massy 91300, France
3
Banook group, 84 avenue du XXeme Corps, Nancy 54000, France
Type 2 diabetes mellitus (T2DM) is characterized by beta-cell dysfunction and peripheral insulin resistance leading to hyperglycemia [1, 2]. Chronic hyperglycemia has been associated with the development of both macrovascular and microvascular complications [3]. Recent estimates indicate that there were 422 million adults in the world with T2DM in 2014 [4]. This chronic and progressive disease requires long-term lifestyle modifications and pharmacologic management to maintain effective glycemic control [5]. Unfortun
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