Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosen
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Research Article Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan Pierre-Eric Juif,1,3 Jasper Dingemanse,1 Christine Voors-Pette,2 and Mike Ufer1
Received 19 June 2020; accepted 11 July 2020 Abstract. This study investigated the potential QT liability of the selective endothelin-1 A receptor antagonist clazosentan at a therapeutic (20 mg/h) and supratherapeutic (60 mg/h) intravenous (i.v.) dose. A randomized, placebo- and moxifloxacin-controlled, double-blind, 3period, crossover study was conducted in 36 healthy subjects receiving clazosentan (20 mg/h followed by 60 mg/h i.v. for 3 h each), placebo (i.v. for 6 h), and moxifloxacin (single oral dose of 400 mg concomitantly with placebo i.v. for 6 h). At least three replicate ECGs were extracted from Holter recordings at predefined time points from 1 h pre-dose to 24 h after end of infusion. Pharmacokinetic blood sampling was performed for concentration/QT analysis (primary endpoint). For moxifloxacin, the lower bound of the 90% confidence interval (CI) of baseline- and placebo-corrected QTcF (ΔΔQTcF) was > 5 ms at its maximum plasma concentration together with a positive slope of the concentration/QT regression line demonstrating assay sensitivity. For clazosentan, time of peak exposure preceded maximum ΔΔQTcF by 4 h indicating delayed QT-prolonging effects leading to invalidity of the concentration/QT analysis. The secondary by-time-point analysis revealed QT liability of clazosentan (i.e., upper bound of 90% CI ΔΔQTcF > 10 ms). Delayed QT prolongation (i.e., hysteresis) was predominantly observed in subjects with nausea and vomiting, potentially caused by vagal reaction and/or decreases in potassium concentration. By contrast, there was no association with other adverse events, food intake, or concomitant medication. In conclusion, clazosentan at therapeutic and supratherapeutic doses has QT liability with hysteresis effects being associated with nausea and vomiting. KEY WORDS: clazosentan; concentration/QT analysis; endothelin; hysteresis; QT interval; vomiting.
INTRODUCTION Endothelin-1 (ET-1) is one of the most potent vasoconstrictors and ET-1 concentrations are increased in a number of different diseases including aneurysmal subarachnoid hemorrhage (aSAH) (1,2). Changes of the ET-receptor expression and function in the wall of the cerebral arteries are a causal factor for the development of cerebral vasospasm, which is considered as one of the major causes of morbidity and mortality in patients with aSAH (3). Nimodipine is the only approved treatment of aSAHassociated vasospasm, but has limited efficacy with respect to major clinical outcomes (e.g., mortality, delayed cerebral
Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00485-6) contains supplementary material, which is available to authorized users. 1
Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123, Allschwil, Switzerland. 2 QPS
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