The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death. Consequently, there has been a paradigm shift to assess a compound’s cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.

For nearly 2 decades, regulators have adopted a harmonized approach to drug development, which has succeeded in bringing new pharmaceuticals to market without significant cardiac liability.Ushered in by technological advancements and better understanding of cellular electrophysiology, the initial paradigm detailed in the 2005 International Conference for Harmonization E14 and S7B documents has undergone evolutionary changes designed to streamline drug development and improve regulatory decision-making and product labeling. The intent of this review is to summarize the new US Food and Drug Administration (FDA) Question and Answer update from August 2020 and key messaging from a subsequent FDA webinar describing best practices for preclinical and clinical data integration into a QT risk prediction model.

Introduction: hERG assays and thorough ECG trials have been mandated since 2005 to evaluate the QT interval and potential proarrhythmic risk of new chemical entities. The high cost of these studies and the shortcomings inherent in these binary and limited approaches to drug evaluation have prompted regulators to search for more cost effective and mechanistic paradigms to assess drug liability as exemplified by the CiPA initiative and the exposure response ICH E14(R3) guidance document. Areas covered: This review profiles the changing regulatory landscape as it pertains to early drug development and outlines the analyses that can be performed to characterize preclinical and early clinical cardiovascular risk. Expert commentary: It is further acknowledged that the narrow focus on the QT interval needs to be expanded to include a more comprehensive evaluation of cardiovascular risk since unanticipated off target effects have led to the withdrawal of multiple drugs after they had been approved and marketed.

The assessment of a drug’s cardiac liability has undergone considerable metamorphosis by regulators since International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14 guideline was introduced in 2005. Drug developers now have a choice in how proarrhythmia risk can be evaluated; the options include a dedicated thorough QT (TQT) study or exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early clinical development. The alternative approach of ER modeling was incorporated into a guidance document in 2015 as a primary analysis tool which could be utilized in early phase dose escalation studies as an option to perform a dedicated TQT trial. This review will describe the current state of ER modeling of intensive ECG data collected during early clinical drug development; the requirements with regard to the use of a positive control; and address the challenges and opportunities of this alternative approach to assessing QT liability.

Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.