Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block
Jose Vicente1,2,3, Lars Johannesen1, Meisam Hosseini1,2
1Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
Insights
The J-Tpeakc interval on ECGs can identify late sodium current block, a key factor in drug safety. This finding aids in assessing proarrhythmic risk for new medications by distinguishing multichannel block from selective hERG channel block.
Area of Science:
- Cardiovascular pharmacology
- Clinical electrocardiology
- Drug safety assessment
Background:
- Drugs blocking the hERG channel and inward currents do not cause torsade de pointes.
- Identifying electrocardiogram (ECG) signs of late sodium current block is crucial for assessing drug proarrhythmic risk.
- The CiPA initiative requires new ECG biomarkers for preclinical drug development to detect unexpected ion channel effects.
Purpose of the Study:
- To evaluate ECG morphology biomarkers for detecting late sodium current block during QTc prolongation.
- To compare the efficacy of different ECG biomarkers in identifying late sodium current block.
Main Methods:
- Analysis of a clinical trial involving a selective hERG blocker (dofetilide) alone and with late sodium current blockers (lidocaine, mexiletine).
- Assessment of eight ECG morphology biomarkers, including J-Tpeakc, QTc, and T-wave flatness.
- Statistical comparison of biomarker performance using Area Under the Curve (AUC).
Main Results:
- Late sodium current block significantly impacts the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and T-wave flatness.
- J-Tpeakc demonstrated superior performance in detecting late sodium current block compared to QTc alone (AUC: 0.83 vs. 0.72, p<0.001).
Conclusions:
- The J-Tpeakc interval effectively differentiates drug-induced multichannel block involving late sodium current from selective hERG channel block.
- Future ECG-based drug safety assessments should incorporate J-Tpeakc to identify late sodium current block.
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.
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