Differentiating Drug-Induced Multichannel Block on the Electrocardiogram: Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil

Abstract

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.

Comparison of Two Highly Automated ECG Algorithms for Detection of Drug‐Induced Cardiac Ion Channel Block

“…The pharmacokinetic characteristics were previously reported. 3 Dofetilide and quinidine had maximum concentrations occurring at 2.5 h and 2.0 h with mean half-lives of 7.2 ± 1.1 (±S.D) and 7.8 ± 1.5h, respectively. Mean peak ranolazine concentrations occurred at 4.0 h with a half-life of 7.5 ± 2.3 h and verapamil peak concentrations occurred at 1.0 h with a mean half-life of 10.4 ± 3.2 h.…”

“…3 The baselines ECG values determined in this study by the FDA and alternative software algorithms were, respectively: Heart rate 56.0 ± 6.7 vs. 56.0 ± 6.6 bpm; QTcF 395.6 ± 17 vs. 394.1 ± 16.4 ms; J-T peak c 224.1 ± 19.8 vs. 227.6 ± 21.2 ms; T peak – T end 74.3 ± 6.9 vs. 77.6 ± 5.8 ms.…”

“…In this study we retrospectively examined data from a randomized controlled clinical trial conducted by the FDA 3 for potential new biomarkers that can differentiate multichannel block and improve assessment of arrhythmia risk compared to QTc alone. Our study objectives were to determine if use of an alternative software algorithm could corroborate the FDA analysis and to examine the nature of differences in results of the two algorithms.…”

“…3 The four drugs prospectively studied in a randomized, crossover design, inhibit the human ether-a-go-go-related gene (hERG) potassium channel, I Kr , either alone, or in combination with varying degrees of inhibition on the L-type calcium, and early and late sodium inward currents. Dofetilide was chosen as a specific hERG blocker with a high incidence of torsade.…”

“…4 Using only supine resting ECGs, it was shown that, unlike QTc, early and late measures of repolarization (heart rate–corrected global J-T peak (c) and global T peak -T end , respectively) could differentiate pure hERG block associated with a high incidence of torsade risk, from multichannel block of hERG and either calcium or late sodium currents, which is associated with lower risk. 3 …”