Preclinical strategies to assess QT liability and torsadogenic potential of new drugs: The role of experimental models

Abstract

The recognition of QT prolongation and torsade de pointes (TdP) in humans has resulted in the re-labeling of some drugs and the removal of others from the market in the past decade. Recent regulatory guidelines have recommended a battery of preclinical tests to assess a new drug for the QT liability in humans. The assessment includes the effect of a drug on: 1) the ionic current in stable cell lines expressing hERG channel; 2) action potential duration (APD) measured in isolated ventricular tissues; 3) the QTc interval and TdP in animals in vivo; and 4) APD, the QT interval, transmural dispersion of repolarization (TDR) and TdP potential in the isolated arterially-perfused ventricular wedge preparation. Because a noncardiac drug with an incidence of TdP even less than 0.1% can be potentially removed from the market, the experimental models used for preclinical testing have to be high sensitive and specific to the signals related to TdP. Among available experimental models, the rabbit left ventricle wedge preparation exhibits a high sensitivity and a high specificity in the identification of compounds positive and negative for QT prolongation and TdP. This is attributed to the fact that the preparation demonstrates strong signals related to QT prolongation in response to even a weaker QT prolonging agent. Signals specifically pertinent to the development of TdP, ie, early afterdepolarization (EAD) and an increase in TDR can be detected as well. The preclinical data obtained from the wedge preparation correlate well with clinical outcomes.