Impact of study design on proarrhythmia prediction in the SCREENIT rabbit isolated heart model.
BACKGROUND
Prediction of the propensity of a compound to induce Torsades de Pointes continues to be a formidable challenge to the pharmaceutical industry. Development of an in vitro model for assessment of proarrhythmic potential offers the advantage of higher throughput and reduced compound quantity requirements when compared to in vivo studies. A rabbit isolated heart model (SCREENIT) has been reported to identify compounds with proarrhythmic potential based on the observance of compound-induced triangulation and instability of the monophasic action potential (MAP), ectopic beats, and reverse-use dependence of prolongation of the MAP duration. Previous reports have indicated that this model qualitatively identifies proarrhythmic compounds and suggest the use of this model to assign safety margins for human clinical use. The intent of this series of studies was to evaluate the impact of study design on the proarrhythmic concentration predicted by this model.


METHODS
Nine compounds of varying proarrhythmic potential and a negative control were tested in a blinded fashion using a series of different experimental protocols: Compounds were tested at multiple concentration ranges and extended perfusion times were also evaluated.


RESULTS
In general when the dataset is viewed as a whole, the model did identify proarrhythmic compounds, however the concentration at which action potential prolongation, triangulation, instability, reverse-use dependence and ectopic beats occurred often varied based on the concentration range selected. Further analysis using extended compound perfusion times demonstrated that variability may be due in part to lack of adequate equilibration of compound with the cardiac tissue.


CONCLUSIONS
We report that the model correctly identified proarrhythmic agents in a qualitative manner, but that study design impacts the proarrhythmic concentration derived from the model.
Steidl-Nichols
Jill V
JV
Global Safety Pharmacology, Pfizer Global Research and Development, La Jolla Laboratories, 10646 Science Center Drive, San Diego, CA 92121, USA. jill.steidl@pfizer.com
Hanton
Gilles
G
Leaney
Joanne
J
Liu
Ruei-Che
RC
Leishman
Derek
D
McHarg
Aileen
A
Wallis
Rob
R
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002317:Cardiovascular Agents / Q000009:adverse effects*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D022062:Electrophysiologic Techniques, Cardiac; D006329:Heart Conduction System / Q000187:drug effects; D008954:Models, Biological; D011237:Predictive Value of Tests; D011817:Rabbits
D002317:Cardiovascular Agents