A rabbit Langendorff heart proarrhythmia model: Predictive value for clinical identification of Torsades de Pointes

Abstract

Background and purpose:The rabbit isolated Langendorff heart model (SCREENIT) was used to investigate the proarrhythmic potential of a range of marketed drugs or drugs intended for market. These data were used to validate the SCREENIT model against clinical outcomes.Experimental approach:Fifty-five drugs, 3 replicates and 2 controls were tested in a blinded manner. Proarrhythmia variables included a 10% change in MAPD 60, triangulation, instability and reverse frequency-dependence of the MAP. Early after-depolarisations, ventricular tachycardia, TdP and ventricular fibrillation were noted. Data are reported at nominal concentrations relative to EFTPC max. Proarrhythmic scores were assigned to each drug and each drug category.Key results:Category 1 and 2 drugs have the highest number of proarrhythmia variables and overt proarrhythmia while Category 5 drugs have the lowest, at every margin. At 30-fold the EFTPC max, the mean proarrhythmic scores are: Category 1, 101±24; Category 2, 101±14; Category 3, 72±20; Category 4, 59±16 and Category 5, 22±9 points. Only drugs in Category 5 have mean proarrhythmic scores, below 30-fold, that remain within the Safety Zone.Conclusions and Implications:A 30-fold margin between effects and EFTPC max is sufficiently stringent to provide confidence to proceed with a new chemical entity, without incurring the risk of eliminating potentially beneficial drugs. The model is particularly useful where compounds have small margins between the hERG IC 50 and predicted EFTPC max. These data suggest this is a robust and reliable assay that can add value to an integrated QT/TdP risk assessment. © 2006 Nature Publishing Group All rights reserved.