title: Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil.
abstract: BACKGROUND
  Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology.
  
  
  RESULTS
  Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide).
  
  
  CONCLUSIONS
  T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk.
  
  
  BACKGROUND
  URL: http://clinicaltrials.gov/ Unique identifier: NCT01873950.
authors: Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD (J.V., L.J., E.P., D.G.S.) Division of Cardiovascular and Renal Products, Office of New Drugs, CDER, US FDA, Silver Spring, MD (J.V., N.S.) BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain (J.V., E.P.).
authors: Jose
authors: J
authors: Vicente
authors: Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD (J.V., L.J., E.P., D.G.S.) Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (L.J., D.G.S.).
authors: Lars
authors: L
authors: Johannesen
authors: Spaulding Clinical Research, West Bend, WI (J.W.M.).
authors: Jay W
authors: JW
authors: Mason
authors: Zenas Technologies, New Orleans, Louisiana (W.J.C.).
authors: William J
authors: WJ
authors: Crumb
authors: Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD (J.V., L.J., E.P., D.G.S.) BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain (J.V., E.P.) Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain (E.P.).
authors: Esther
authors: E
authors: Pueyo
authors: Division of Cardiovascular and Renal Products, Office of New Drugs, CDER, US FDA, Silver Spring, MD (J.V., N.S.).
authors: Norman
authors: N
authors: Stockbridge
authors: Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD (J.V., L.J., E.P., D.G.S.) Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (L.J., D.G.S.).
authors: David G
authors: DG
authors: Strauss
mesh_terms: D000328:Adult; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018592:Cross-Over Studies; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D010627:Phenethylamines / Q000097:blood / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D000069458:Ranolazine / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D000069458:Ranolazine; D014700:Verapamil; D011802:Quinidine; C063533:dofetilide
keywords: electrocardiography; ion channels; long‐QT syndrome; pharmacology; torsade de pointes