Developing a strategy for the nonclinical assessment of proarrhythmic risk of pharmaceuticals due to prolonged ventricular repolarization.

The aspects for developing a strategy for the preclinical testing of drug candidates for proarrhythmic potential are presented. The rationale for such a strategy reflects primarily the needs for efficient and scientifically based drug development and also attempts to anticipate the possible outcomes of the currently ongoing regulatory activity (ICH S7b and E14). Whereas a wealth of new data have emerged over the past few years, demonstrating the utility of test systems for detecting drug effects on myocardial repolarization, the current regulatory trend appears to not use such data for the clinical trial design or risk assessment. Nevertheless, certain types of preclinical tests are highly recommended for optimizing drug development, despite their still questionable regulatory acceptance. This includes (1) testing for blockade of I(Kr) or hERG-mediated potassium current in heterologous cell systems, (2) measurement of effects on the myocardial action potential in vitro; and (3) assessment of effects on the ECG in a well-conducted in vivo study. Due to their requirement for little compound, the first two in vitro tests lend themselves for early safety testing of drug candidates still in the lead optimization phase of drug discovery; together, they form a useful and predictive in vitro assessment. This strategy is not new but reflects what was initially suggested by the Committee for Proprietary Medicinal Products (CPMP) some years ago. However, the validation of such a strategy and its utility in drug development is now well established and recommended, independent from future regulatory requirements.