chapter  4
24 Pages

Markers for Cardiac Repolarization and Risk Assessment

The determination of whether an investigative pharmaceutical agent prolongs

repolarization in the heart (an effect equivalent to prolongation of the QT interval

on the surface electrocardiogram) has become a mandatory step in the drug

development process. Such a determination takes considerable preclinical and

clinical screening of cardiac biomarkers. This determination is rapidly evolving

as an increasing body of knowledge is gained on the mechanisms by which drugs

prolong cardiac repolarization and on identification of high-risk populations.

Failure to recognize the potential of an investigative agent to prolong cardiac

repolarization places future drug recipients at risk for life-threatening ventricular

arrhythmias, particularly a distinctive polymorphic ventricular tachycardia

termed “torsade de pointes.” Appropriate market withdrawal of the drug may

result. In this chapter, an approach to understanding the regulatory background,

mechanisms, and the preclinical and clinical assessment of cardiac biomarkers in

the determination of drug effects on cardiac repolarization is undertaken.