Comparison of the QT interval response during sinus and paced rhythm in conscious and anesthetized beagle dogs.
BACKGROUND
The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles.


METHODS
Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms).


RESULTS
In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording.


CONCLUSIONS
All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.
Ollerstam
Anna
A
Safety Pharmacology, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. anna.ollerstam@astrazeneca.com
Visser
Sandra A G
SA
Duker
Göran
G
Forsberg
Tomas
T
Persson
Anna H
AH
Nilsson
Lars B
LB
Björkman
Jan-Arne
JA
Gabrielsson
Johan
J
Al-Saffar
Ahmad
A
D000758:Anesthesia; D000818:Animals; D001372:Aza Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D002304:Cardiac Pacing, Artificial; D020117:Cisapride / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D003243:Consciousness; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D005260:Female; D024841:Fluoroquinolones; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D023421:Models, Animal; D000077266:Moxifloxacin; D010627:Phenethylamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D012849:Sinoatrial Node / Q000187:drug effects / Q000503:physiopathology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D013686:Telemetry / Q000379:methods*; D016593:Terfenadine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D013997:Time Factors
D001372:Aza Compounds; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D010627:Phenethylamines; D011804:Quinolines; D013449:Sulfonamides; D016593:Terfenadine; C063533:dofetilide; D000077266:Moxifloxacin; D020117:Cisapride