title: 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abstract: Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market.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-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.
authors.affiliation: Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.|Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Johannesen
authors.affiliation: Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.|Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.|BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Vicente
authors.affiliation: Spaulding Clinical, West Bend, Wisconsin, USA.|University of Utah, Salt Lake City, Utah, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Mason
authors.affiliation: Spaulding Clinical, West Bend, Wisconsin, USA.
authors.forename: C
authors.initials: C
authors.lastname: Erato
authors.affiliation: Spaulding Clinical, West Bend, Wisconsin, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sanabria
authors.affiliation: Spaulding Clinical, West Bend, Wisconsin, USA.
authors.forename: K
authors.initials: K
authors.lastname: Waite-Labott
authors.affiliation: Frontage Laboratories, Exton, Pennsylvania, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hong
authors.affiliation: Frontage Laboratories, Exton, Pennsylvania, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: Frontage Laboratories, Exton, Pennsylvania, USA.
authors.forename: P
authors.initials: P
authors.lastname: Guo
authors.affiliation: Frontage Laboratories, Exton, Pennsylvania, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mutlib
authors.affiliation: Frontage Laboratories, Exton, Pennsylvania, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Zenas Technologies, Metairie, Louisiana, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Crumb
authors.affiliation: Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: K
authors.initials: K
authors.lastname: Blinova
authors.affiliation: Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: D
authors.initials: D
authors.lastname: Chan
authors.affiliation: Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Stohlman
authors.affiliation: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Florian
authors.affiliation: Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.|Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ugander
authors.affiliation: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: N
authors.initials: N
authors.lastname: Stockbridge
authors.affiliation: Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA.|Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: D G
authors.initials: DG
authors.lastname: Strauss
mesh_terms: D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000627:therapeutic use; D018592:Cross-Over Studies; D004110:Diltiazem / Q000493:pharmacokinetics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008012:Lidocaine / Q000493:pharmacokinetics / Q000627:therapeutic use; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D008801:Mexiletine / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077266:Moxifloxacin; D010627:Phenethylamines / Q000009:adverse effects; D011446:Prospective Studies; D026941:Sodium Channel Blockers / Q000009:adverse effects*; D013449:Sulfonamides / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D010627:Phenethylamines; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D008801:Mexiletine; D008012:Lidocaine; D004110:Diltiazem; C063533:dofetilide; D000077266:Moxifloxacin