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

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Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market.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-T peak (J-T peak 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 Correspondence: DG Strauss David.Strauss@fda.hhs.gov. Additional Supporting Information may be found in the online version of this article.Author Contributions: All authors have contributed as follows: protocol development (L.J., J.V., J.W.M., C.S., K.W.L., J.F., N.S., D.G.S.), data collection (C.E., C.S., K.W.L., M.H., J.L., P.G., A.M., J.W., W.J.C.), data analysis (L.J., J.V., J.F., D.G.S.), and preparing the manuscript (L.J., D.G.S.). All authors discussed the results and implications and commented on the manuscript. Conflict of HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript hERG potassium channel block and assessment of J-T peak c may add value beyond only assessing QTc.Drug-induced QT prolongation increases the risk for torsade de pointes, a potentially fatal ventricular arrhythmia. 1 QT prolongation and increased risk for torsade de pointes have resulted in 14 drugs being removed from the market worldwide. 2 Furthermore, many drugs remain on the market with a known torsade de pointes risk, including numerous antibiotics, antimalarial, antiviral, psychiatric, oncology, and cardiac drugs. 3 At the same time, the current regulatory paradigm for assessing drug effects on cardiac repolarization is preventing potentially effective medicines from reaching the market, sometimes inappropriately. 2 To address this, the US Food and Drug Administration (FDA) and multiple public-private partnerships are studying novel approaches to assess the cardiac safety of new drugs with a Comprehensive in vitro Proarrhythmia Assay and in Phase 1 clinical trials. 4,5 Essential to the novel approaches is a focus on understanding mechanisms by studying the effects of drugs on multiple cardiac ion channels, which can be either proarrhythmic or antiarrhythmic depending on the combination. 6Almost all drugs on the market that can cause torsade de pointes block the hERG potassium channel 7 and prolong the QT interval of the electrocardiogram (ECG). 8 However, some drugs block the hERG potassium channel and prolong QT with a minimal torsade de pointes risk (e....

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