A rabbit Langendorff heart proarrhythmia model: predictive value for clinical identification of Torsades de Pointes.
OBJECTIVE
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.


METHODS
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.


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
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.
Lawrence
C L
CL
Safety Pharmacology, Safety Assessment UK, AstraZeneca R&D, Macclesfield, Cheshire, UK. chris.lawrence@astrazeneca.com
Bridgland-Taylor
M H
MH
Pollard
C E
CE
Hammond
T G
TG
Valentin
J-P
JP
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000145:classification; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects; D023421:Models, Animal; D011237:Predictive Value of Tests; D051381:Rats; D015203:Reproducibility of Results; D018570:Risk Assessment; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D015507:Drugs, Investigational; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human