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Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market.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 AdultABSTRACT
Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.
