Abstract
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.
Highlights
In 1895, Einthoven developed the human electrocardiogram (ECG) and described the PR segment, QRS complex and the T wave while a decade later he and Lewis recognized the existence of U waves [1]
It is evident from the foregoing discussion that the QTc interval, despite its modest positive predictive value for Torsades de Pointes (TdP) and ventricular arrhythmias, continues to occupy a central focus of regulators as a surrogate marker for proarrhythmic risk during drug development
There has been an evolution in how stakeholders are approaching cardiac liability as embodied by the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with its advanced preclinical assays, and the emergence of concentration QT (cQT) as a primary analysis tool in dose escalation studies
Summary
In 1895, Einthoven developed the human electrocardiogram (ECG) and described the PR segment, QRS complex and the T wave while a decade later he and Lewis recognized the existence of U waves [1]. Additional classes of medications including antibiotics and psychotropic drugs were linked to TdP and a number of these agents were subsequently withdrawn by the Food and Drug Administration (FDA) [9] In response to these events, government regulators and the pharmaceutical industry realized that a comprehensive evaluation of the QT interval and arrhythmia risk should be incorporated into a new compound’s development program. This document was written in response to multiple reports of non-antiarrhythmic drugs prolonging the QT interval on the ECG resulting in TdP. It formed the basis for regulatory agencies worldwide to focus attention on the arrhythmic potential of drugs that were previously deemed to be safe. To date ICH S7B has not been formally amended, whereas ICH E14 has been updated with Q&A responses on multiple occasions in 2008, 2012, 2014 and 2015 [12] but has not been officially revised in entirety
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