The Potential Role of the J‐T_peak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

“…QTc prolongers with predominant hERG block prolonged J‐Tpeakc, but those with balanced multichannel block did not prolong J‐Tpeakc 38,56‐59 . This biomarker was proposed not to be an independent proarrhythmia marker, but part of an integrated risk assessment checking for missed or unanticipated effects from the in vitro / in silico proarrhythmia model 60,61 …”

Transdermal Testosterone Attenuates Drug‐Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men

“…J-T peak c corresponds to early ventricular repolarization and has been used to differentiate QT-prolonging drugs that inhibit inward currents, such as calcium and late sodium from predominant I Kr inhibitors. 10,11 T peak -T end corresponds to late repolarization, predominantly regulated by I Kr and I Ks . The fact that testosterone attenuated drug-induced lengthening of both early and late repolarization suggests that it could be administered to older men with other risk factors for QT prolongation who require therapy with potentially proarrhythmic drugs that solely inhibit I Kr as well as those that prolong early repolarization via modulation of other ion currents.…”

“…J‐T peak c corresponds to early ventricular repolarization and has been used to differentiate QT‐prolonging drugs that inhibit inward currents, such as calcium and late sodium from predominant I Kr inhibitors 10,11 . T peak ‐T end corresponds to late repolarization, predominantly regulated by I Kr and I Ks .…”

“…In recent years, interest has grown regarding assessment of drug effects on components of the QT interval. Multichannel drug effects can be differentiated through assessment of early ventricular repolarization, represented by J‐T peak , and late repolarization, represented by T peak ‐T end 10,11 . In addition, T peak ‐T end and the T peak ‐T end /QT interval ratio are markers of transmural dispersion of repolarization (TDR), 12 enhancement of which is associated with increased proarrhythmia risk.…”

The International Council for Harmonisation and a Case Study in Regulatory Science

“…Additional clinical concern arises because this arrhythmia also has potentially catastrophic consequences-it can occasionally progress to ventricular fibrillation and sudden cardiac death. 11 Precipitating risk factors include advanced age, female sex, structural heart disease, metabolic and electrolyte abnormalities including hypokalemia and hypocalcemia, bradycardia and cardiac conduction disease, increased drug bioavailability due to renal or hepatic impairment, genetic predisposition (a clinical condition called long QT syndrome, which in itself is associated with torsade), and the co-prescription of loop diuretics and other proarrhythmic drugs. [12][13][14] As Link and colleagues observed, "One of the most feared complications in medicine is sudden death caused by drug-induced proarrhythmia.…”