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.

Methods and 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.

Trial registration: NCT02308748 and NCT01873950.

Conflict of interest statement

PT Sager has consulting agreements with Biomedical Systems, Charles River, and iCardiac. The other authors report no conflicts. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. ECG “signature” of selective hERG potassium channel block.

The ECG “signature” of selective hERG potassium channel block is shown as the relationship between predicted drug-induced placebo-corrected changes from baseline in QTc and (a) J-Tpeakc, (b) Tpeak-Tend, (c) 30% of early repolarization duration, (d) 30% of late repolarization duration, (e) T-wave flatness, (f) T-wave asymmetry and (g) T-wave amplitude. Average predictions (dots) and 95% confidence intervals (horizontal and vertical lines) are from the concentration-dependent models for QTc (x axis) and the different T-wave morphology biomarkers (y axis) at 25% increments of the population’s Cmax for dofetilide alone (light gray) and moxifloxacin (yellow) arms in this study together with the dofetilide arm from previous clinical study (Dofetilide—Study 1) [10, 12]. QTc, Fridericia’s heart rate corrected QT; J-Tpeakc, heart rate corrected J-Tpeakc interval.

Fig 2. ECG “signatures” of dofetilide, ranolazine, mexiletine + dofetilide and lidocaine + dofetilide.

The ECG “signatures” of dofetilide (light gray), ranolazine (blue), mexiletine + dofetilide (orange) and lidocaine + dofetilide (green) are shown as the relationship between predicted drug-induced placebo-corrected changes from baseline in QTc and (a) J-Tpeakc, (b) Tpeak-Tend, (c) 30% of early repolarization duration, (d) 30% of late repolarization duration, (e) T-wave flatness, (f) T-wave asymmetry and (g) T-wave amplitude. Average predictions (dots) and 95% confidence intervals (horizontal and vertical lines) are shown from the concentration-dependent models for QTc (x axis) and the different T-wave morphology biomarkers (y axis) at 25% increments of the population’s Cmax for dofetilide alone (light gray) arm in FDA study 2 and ranolazine (blue) arm from FDA study 1 [10, 12]. Average (dots) and 95% confidence intervals (vertical and horizontal bars) of placebo-corrected changes from baseline are shown for mexiletine + dofetilide (orange) and lidocaine + dofetilide (green). QTc, Fridericia’s heart rate corrected QT; J-Tpeakc, heart rate corrected J-Tpeakc interval.

Fig 3. Cohen’s d effect size for each ECG biomarker.

Cohen’s d effect size for each ECG biomarker for mexiletine + dofetilide and lidocaine + dofetilide vs. dofetilide alone.

Fig 4. ROC curves for multiple logistic regression models.

QTc, Fridericia’s heart rate corrected QT interval; J-Tpeakc, heart rate corrected J-Tpeakc interval; T-wave flatness, heart rate corrected T-wave flatness. Area under the curve of each model reported in parenthesis.

Fig 5. Decision tree.

The decision tree classifies the drug effects on any ECG from any time point based on the time-matched placebo-corrected changes from baseline (ΔΔ) as selective of predominant hERG potassium channel block (right bin), multichannel block (left bin) or inconclusive (middle bin). More specifically, if ΔΔJ-Tpeakc is greater than 9ms the ECG is classified as predominant or selective hERG potassium channel block. If ΔΔ J-Tpeakc is less than or equal to 9ms and ΔΔQTc less than or equal to 29ms, then the ECG is classified as multichannel block. Otherwise the classification is inconclusive. The number of ECGs from each class in the training set is reported in parenthesis on top of each class bin. The percentage of ECGs correctly classified within each class is reported below each class bin. See text for more details on classification performance in both training (hERG [dofetilide and moxifloxacin] vs. multichannel [dofetilide + mexiletine and dofetilide + lidocaine]) and validation (hERG [dofetilide and quinidine] vs. multichannel [ranolazine and verapamil]) sets. QTc, Fridericia’s heart rate corrected QT interval; J-Tpeakc, heart rate corrected J-Tpeak interval; hERG, selective or strong hERG potassium channel block; Multichannel, inward (late sodium or calcium) current and hERG potassium channel block.