Vicente Jose, Johannesen Lars, Hosseini Meisam, Mason Jay W, Sager Philip T, Pueyo Esther, Strauss David G
Division 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.
Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, United States of America.
PLoS One. 2016 Dec 30;11(12):e0163619. doi: 10.1371/journal.pone.0163619. eCollection 2016.
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.
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).
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.
NCT02308748 and NCT01873950.
通过阻断人醚 - 乌头碱相关基因（hERG）钾通道来延长心电图（ECG）上心率校正QT间期（QTc），同时还阻断内向电流（晚钠电流或L型钙电流）的药物与尖端扭转型室速无关（如雷诺嗪和维拉帕米）。因此，识别晚钠电流阻断的心电图征象有助于确定新药的促心律失常风险。一种新的药物研发心脏安全性范式（“CiPA”计划）将涉及对多种人类心脏离子通道进行临床前评估，并且需要心电图生物标志物来确定在人体中是否存在意外的离子通道效应。
在本研究中，我们通过分析一项临床试验来评估八种心电图形态生物标志物在QTc延长情况下检测晚钠电流阻断的能力，该试验中单独给予一种选择性hERG钾通道阻滞剂（多非利特），然后与两种晚钠电流阻滞剂（利多卡因和美西律）联合使用。我们证明，晚钠电流阻断对心率校正J波峰至T波峰间期（J-Tpeakc）影响最大，其次是QTc，然后是T波平坦度。此外，与单独使用QTc相比，J-Tpeakc是唯一能改善晚钠电流阻断存在检测的生物标志物（曲线下面积分别为0.83对0.72，p<0.001）。
对J-Tpeakc间期的分析可以区分药物诱导的涉及晚钠电流的多通道阻断与选择性hERG钾通道阻断。未来评估药物对心电图上心脏离子通道电流影响的方法应使用J-Tpeakc来检测晚钠电流阻断的存在。
NCT02308748和NCT01873950。
