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Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market.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.

Figure 1

Late sodium current (shaded) correlates with the plateau of the action potential and early part of repolarization on the ECG, from J-point to peak of the T-wave.

Figure 2

Morning, afternoon, and evening doses for each of the five treatment periods. Below the table, an illustration of the plasma drug level is shown to indicate when oral and intravenous dosing took place as well as when ECGs and plasma samples were taken (in hours after first oral dose). Dof, dofetilide; mex, mexiletine; lido, lidocaine; mox, moxifloxacin; dil, diltiazem.

Figure 3

Changes shown in QTc for dofetilide alone (a), mexiletine combined with dofetilide (b), and lidocaine combined with dofetilide (c), while the lower part of the panels show the concentration of dofetilide (green) and mexiletine or lidocaine (blue) in their respective panels. The error bars represent 95% confidence intervals (CI). (d) Example ECGs from a subject during the evening dose of placebo, dofetilide, mexiletine combined with dofetilide, and lidocaine combined with dofetilide. The remaining bottom panels (e and f) show relative change compared to dofetilide alone for mexiletine combined with dofetilide (e) and lidocaine combined with dofetilide (f), where only the timepoint at the end of the loading dose is shown and points are shifted slightly for each interval to avoid overlap. Dof, dofetilide; mex, mexiletine; lido, lidocaine. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

(a) The plasma drug concentration-dependent analysis for QTc, J-T_peakc, and T_peak-T_end, from left to right for dofetilide combined with mexiletine (red) or lidocaine (blue), and (b) for moxifloxacin and diltiazem. The solid line and shaded area reflects the fit of a linear model between drug concentration (dofetilide in panel a and moxifloxacin in panel b) and change in placebo and baseline-corrected change in each ECG interval. The points with error bars (95% confidence intervals (CIs)) reflect the maximum change when mexiletine is combined with dofetilide (red) or lidocaine is combined with dofetilide (blue) for panel a and moxifloxacin combined with diltiazem (red) in panel b. Dof, dofetilide; mex, mexiletine; lido, lidocaine; mox, moxifloxacin; dil, diltiazem. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 5

The results of the patch clamp experiments for dofetilide (a), mexiletine (b), lidocaine (c), moxifloxacin and M2 metabolite (d), and diltiazem (e) for hERG (red), late sodium (green), calcium (blue), and I_Ks (purple). The lines in each plot correspond to a fit between the measured relative reduction in current and drug concentration. The error bars denote ± SE. The vertical dashed lines in each panel correspond to the range of observed clinical plasma concentrations, corrected for protein binding, and the solid line is the population average maximum plasma concentration in the clinical trial. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]