Table 1.
Baseline characteristics.
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.
Table 2.
Cmax time-points (Tmax) and plasma drug concentrations of mexiletine and lidocaine when given in combination with dofetilide.
Table 3.
Placebo- and baseline-corrected drug-induced ECG changes at Tmax.
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.
Table 4.
Logistic regression by performance.
Fig 5.
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.