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.

METHODS AND 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.

CLINICAL TRIAL REGISTRATION:

URL: http://clinicaltrials.gov/ Unique identifier: NCT01873950.

• Authors: Jose Vicente, Lars Johannesen, Jay W Mason, William J Crumb, Esther Pueyo, Norman Stockbridge, David G Strauss
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 4 Issue 4 (Apr 13 2015) ISSN: 2047-9980 [Electronic] England
• PMID: 25870186 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

• Calcium Channel Blockers
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• Phenethylamines
• Sodium Channel Blockers
• Sulfonamides
• Ranolazine
• Verapamil
• Quinidine
• dofetilide

Topics

• Adult
• Calcium Channel Blockers (pharmacology)
• Cross-Over Studies
• ERG1 Potassium Channel
• Electrocardiography (drug effects)
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors, drug effects)
• Female
• Heart (drug effects)
• Humans
• Long QT Syndrome (chemically induced)
• Male
• Phenethylamines (blood, pharmacology)
• Quinidine (pharmacology)
• Ranolazine (pharmacology)
• Sodium Channel Blockers (pharmacology)
• Sulfonamides (blood, pharmacology)
• Verapamil (pharmacology)