Relevance of in vitro SCREENIT results for drug-induced QT interval prolongation in vivo: a database review and analysis.
BACKGROUND
The use of an isolated rabbit heart model (SCREENIT) to predict drug-induced QTc prolongation in animals was assessed using hERG and telemetry data.


OBJECTIVE
We compiled data from (i) hERG assay (IC50s), (ii) SCREENIT assay (APD60) and (iii) in vivo non-rodent telemetry studies (QTc interval) and evaluated the reliability of APD60 to fit with IC50s and QTc prolongation using the ratio to free plasma level (FPL). Eighty-two compounds were separated into three classes based on hERG IC50s (class I: IC50s< or =1 microM, n=7; class II: IC50s>1 microM to < or =10 microM, n=15; class III: IC50s>10 microM, n=60).


RESULTS
Three class I compounds did not prolong QTc at the FPL equivalent to their IC50s (43% hERG false positives). There were no false positives in SCREENIT. Six class II compounds prolonged the QTc interval. Results showed 40% hERG false negatives and no SCREENIT false negatives. Nine compounds had no effect on QTc, and two prolonged APD60 at an equivalent concentration/FPL (13% false positives). Three class III compounds prolonged QTc at an FPL lower than maximum SCREENIT concentrations (5% false negatives). Four other compounds generated SCREENIT false positive results (7%).


CONCLUSIONS
SCREENIT increased the predictability of preclinical results for QTc prolongation without generating any false positive results in class I (13% in class II). Making decisions without isolated heart data increases the risk for eliminating efficient drugs displaying hERG inhibition.
Dumotier
B M
BM
PreClinical Safety, Novartis Pharma AG, Basel, Switzerland. berengere.dumotier@novartis.com
Deurinck
M
M
Yang
Y
Y
Traebert
M
M
Suter
W
W
D000818:Animals; D016208:Databases, Factual; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008133:Long QT Syndrome / Q000139:chemically induced*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D011817:Rabbits; D015203:Reproducibility of Results; D012189:Retrospective Studies; D013686:Telemetry / Q000379:methods
D051638:Ether-A-Go-Go Potassium Channels; D004364:Pharmaceutical Preparations