Abstract：
INTRODUCTION: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. DISCUSSION: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.
journal_name
J Pharmacol Toxicol Methodsjournal_title
Journal of pharmacological and toxicological methodsauthors
Ollerstam A,Persson AH,Visser SA,Fredriksson JM,Forsberg T,Nilsson LB,Eklund G,Wiklund SJ,Gabrielsson J,Duker G,Al-Saffar Adoi
10.1016/j.vascn.2006.02.009keywords:
subject
Has Abstractpub_date
2007-01-01 00:00:00pages
35-48issue
1eissn
1056-8719issn
1873-488Xpii
S1056-8719(06)00023-2journal_volume
55pub_type
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