title: Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.
abstract: BACKGROUND
  Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.
  
  
  RESULTS
  In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).
  
  
  CONCLUSIONS
  Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.
  
  
  BACKGROUND
  NCT02308748 and NCT01873950.
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.|Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, United States of America.|BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Vicente
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: Lars
authors.initials: L
authors.lastname: Johannesen
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.|Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: Meisam
authors.initials: M
authors.lastname: Hosseini
authors.affiliation: Cardiology Division, University of Utah, Salt Lake City, UT, United States of America.|Spaulding Clinical Research, West Bend, WI, United States of America.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Mason
authors.affiliation: Stanford University, Palo Alto, CA, United States of America.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Sager
authors.affiliation: BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.|Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pueyo
authors.affiliation: Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Strauss
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018592:Cross-Over Studies; D004562:Electrocardiography / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D008133:Long QT Syndrome / Q000378:metabolism; D008297:Male; D008801:Mexiletine / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D002121:Calcium Channel Blockers; D051638:Ether-A-Go-Go Potassium Channels; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D008801:Mexiletine; D008012:Lidocaine; D012964:Sodium; D014700:Verapamil; C063533:dofetilide