A highly sensitive canine telemetry model for detection of QT interval prolongation: studies with moxifloxacin, haloperidol and MK-499.
BACKGROUND
Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the beagle dog telemetry (Integrated Telemetry Services (ITS)) model as a preclinical predictor of QT interval prolongation in humans.


METHODS
Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with moxifloxacin (MOX), haloperidol (HAL), and MK-499, with a toxicokinetic (TK) evaluation in a separate group of dogs. In both cardiovascular and TK studies, MOX (0, 10, 30 and 100 mg/kg), HAL (0, 0.3, 1, 3 mg/kg) and MK-499 (0, 0.03, 0.3 and 3 mg/kg) were administered orally by gavage in 0.5% methylcellulose. Each dog received all 4 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle (0.5% methylcellulose) alone for 4 days.


RESULTS
Significant increases in QT(c) were evident with 10, 30 and 100 mg/kg of MOX (C(max)< or =40 microM), 0.3, 1 and 3 mg/kg of HAL (C(max)< or =0.36 microM) and 0.3 and 3 mg/kg of MK-499 (C(max)< or =825 nM) with peak increases of 45 (20%), 31 (13%), and 45 (19%) ms, respectively (p< or =0.05).


CONCLUSIONS
In conclusion, we have demonstrated that the ITS-telemetry beagle dog exhibits low inherent intra-animal variability and high sensitivity to detect small but significant increases in QT/QT(c) interval ( approximately 3-6%) with MOX, HAL and MK-499 in the same range of therapeutic plasma concentrations attained in humans. Therefore, this dog telemetry model should be considered an important preclinical predictor of QT prolongation of novel human pharmaceuticals.
Chaves
A A
AA
Safety Assessment, Merck Research Laboratories, West Point, PA 19486, USA.
Zingaro
G J
GJ
Yordy
M A
MA
Bustard
K A
KA
O'Sullivan
S
S
Galijatovic-Idrizbegovic
A
A
Schuck
H
H
Christian
D B
DB
Hoe
C M
CM
Briscoe
R J
RJ
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D001372:Aza Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D001578:Benzopyrans / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D024841:Fluoroquinolones; D017408:Guidelines as Topic / Q000592:standards; D006220:Haloperidol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D000077266:Moxifloxacin; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013686:Telemetry / Q000379:methods*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D014150:Antipsychotic Agents; D001372:Aza Compounds; D001578:Benzopyrans; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D010880:Piperidines; D011804:Quinolines; C087257:L 706000; D006220:Haloperidol; D000077266:Moxifloxacin