Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

• Published in: PloS one 2016-12, Vol.11 (12), p.e0163619-e0163619
• Main Authors: Vicente, Jose, Johannesen, Lars, Hosseini, Meisam, Mason, Jay W, Sager, Philip T, Pueyo, Esther, Strauss, David G
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Adult; Analysis; Biological markers; Biology and Life Sciences; Biomarkers; Biomarkers - metabolism; Blocking; Calcium; Calcium Channel Blockers - pharmacology; calcium channels; Calcium channels (L-type); Cardiomyocytes; Clinical trials; Consortia; Cross-Over Studies; decision tree; Dosage and administration; Drug development; Drugs; Echocardiography; EKG; Electrocardiography; Electrocardiography - methods; Engineering and Technology; Engineering research; Ether-A-Go-Go Potassium Channels - metabolism; Female; Food; Heart - drug effects; Heart diseases; Heart rate; Heart Rate - drug effects; Humans; Ion channels; Laboratories; Lidocaine; Lidocaine - pharmacology; Long QT Syndrome - metabolism; Male; Medical equipment; Medicine and Health Sciences; Mexiletine; Mexiletine - pharmacology; Morphology; Pharmacology; Phase I clinical investigation; Phenethylamines - pharmacology; Physical Sciences; Potassium; Potassium Channel Blockers - pharmacology; potassium channels; Prolongation; Research and Analysis Methods; Science; Sodium; Sodium - metabolism; Sodium Channel Blockers - pharmacology; Sulfonamides - pharmacology; Torsades de Pointes - metabolism; Verapamil; Verapamil - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0163619

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