Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias.
BACKGROUND
The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP.


RESULTS
Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max).


CONCLUSIONS
Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.
Liu
Tengxian
T
Main Line Health Heart Center, Wynnewood, PA 19096, USA.
Brown
Barry S
BS
Wu
Ying
Y
Antzelevitch
Charles
C
Kowey
Peter R
PR
Yan
Gan-Xin
GX
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D010477:Perfusion; D011237:Predictive Value of Tests; D011817:Rabbits; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000187:drug effects*