Author:
Lester Robert M.,Paglialunga Sabina,Johnson Ian A.
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.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference99 articles.
1. Ueber die Form des menschlichen Electrocardiogramms
2. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death
3. Rare Cardiac Arrythmias of the Pediatric Age. Ii. Syncopal Attacks Due to Paroxysmal Ventricular Fibrillation. (Presentation of 1st Case in Italian Pediatric Literature);Romano;Clin. Pediatr. (Bologna),1963
4. A New Familial Cardiac Syndrome in Children;Ward;J. Ir. Med. Assoc.,1964
5. Quinidine Syncope
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