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Clin Pharmacol Ther. 2016 Feb;99(2):214-23. doi: 10.1002/cpt.205. Epub 2015 Nov 28.

Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Author information

1
Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
2
Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
3
Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
4
BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
5
Spaulding Clinical, West Bend, Wisconsin, USA.
6
University of Utah, Salt Lake City, Utah, USA.
7
Frontage Laboratories, Exton, Pennsylvania, USA.
8
Zenas Technologies, Metairie, Louisiana, USA.

Abstract

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

PMID:
26259627
PMCID:
PMC5421403
DOI:
10.1002/cpt.205
[Indexed for MEDLINE]
Free PMC Article

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