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Clin Pharmacol Ther ; 99(2): 214-23, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26259627

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Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market.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.


Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Long QT Syndrome/chemically induced , Long QT Syndrome/drug therapy , Sodium Channel Blockers/adverse effects , Adult , Anti-Arrhythmia Agents/pharmacokinetics , 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 , Male , Mexiletine/pharmacokinetics , Mexiletine/therapeutic use , Moxifloxacin , Phenethylamines/adverse effects , Prospective Studies , Sulfonamides/adverse effects , Young Adult
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