A novel approach to data processing of the QT interval response in the conscious telemetered beagle dog.
BACKGROUND
Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model.


METHODS
The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval-heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval.


RESULTS
After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54+/-9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval.


CONCLUSIONS
To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval-heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.
AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. anna.ollerstam@astrazeneca.com
Anna
A
Ollerstam
Anna H
AH
Persson
Sandra A G
SA
Visser
J Magnus
JM
Fredriksson
Tomas
T
Forsberg
Lars B
LB
Nilsson
Göran
G
Eklund
Stig Johan
SJ
Wiklund
Johan
J
Gabrielsson
Göran
G
Duker
Ahmad
A
Al-Saffar
D000465:Algorithms; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D020117:Cisapride / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods; D001330:Electronic Data Processing; D005260:Female; D006220:Haloperidol / Q000493:pharmacokinetics / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis*; D008297:Male; D010627:Phenethylamines / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology; D013686:Telemetry / Q000379:methods; D016593:Terfenadine / Q000493:pharmacokinetics / Q000494:pharmacology
D010627:Phenethylamines; D013449:Sulfonamides; D016593:Terfenadine; D006220:Haloperidol; C063533:dofetilide; D020117:Cisapride