Assessing a Drug's Proarrhythmic Liability: An Overview of Computer Simulation Modeling, Nonclinical Assays, and the Thorough QT/QTc Study

The assessment of proarrhythmic liability has assumed considerable importance in drug development. Such liability is couched in terms of evaluating the degree to which an investigational drug lengthens the QT interval as seen on the surface electrocardiogram (ECG), defined as the time interval from the onset of the Q wave to the offset of the T wave. Two ICH guidelines released in 2005, S7B and E14, addressed nonclinical and clinical proarrhythmic assessments, respectively, and a subsequent E14 Questions and Answers document provided additional commentary on clinical evaluation. While QT prolongation is certainly not the only potential indicator of drug-induced proarrhythmia being investigated, regulatory agencies' adoption of these guidelines lends a current central focus to this area of cardiac safety.This article provides an integrated overview of the molecular biological underpinnings of QT prolongation, nonclinical assays assessing proarrhythmic liability, and the ICH E14 Thorough QT/QTc (TQT) study....