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

• Published in: Clinical pharmacology and therapeutics Vol. 99; no. 2; pp. 214 - 223
• Main Authors: Johannesen, L, Vicente, J, Mason, JW, Erato, C, Sanabria, C, Waite-Labott, K, Hong, M, Lin, J, Guo, P, Mutlib, A, Wang, J, Crumb, WJ, Blinova, K, Chan, D, Stohlman, J, Florian, J, Ugander, M, Stockbridge, N, Strauss, DG
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-02-2016
• Subjects: Adult; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - therapeutic use; Calcium Channel Blockers - pharmacokinetics; Calcium Channel Blockers - therapeutic use; Cross-Over Studies; Diltiazem - pharmacokinetics; Diltiazem - therapeutic use; Drug Therapy, Combination; Electrocardiography - drug effects; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Female; Fluoroquinolones - adverse effects; Heart Rate - drug effects; Humans; Lidocaine - pharmacokinetics; Lidocaine - therapeutic use; Long QT Syndrome - chemically induced; Long QT Syndrome - drug therapy; Male; Medicin och hälsovetenskap; Mexiletine - pharmacokinetics; Mexiletine - therapeutic use; Moxifloxacin; Phenethylamines - adverse effects; Prospective Studies; Sodium Channel Blockers - adverse effects; Sulfonamides - adverse effects; Young Adult
• ISSN: 0009-9236; 1532-6535; 1532-6535
• DOI: 10.1002/cpt.205

Drug‐induced long QT syndrome has resulted in many drugs being withdrawn from the market.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‐Tpeakc) 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‐Tpeakc may add value beyond only assessing QTc.