SENSITIVITY TO DETECT QT INTERVAL PROLONGATION IN A TELEMETRIZED BEAGLE DOG: CARDIOVASCULAR STUDIES WITH MOXIFLOXACIN

Abstract

Moxifl oxacin (MOX) was used to evaluate the sensitivity and validity of the dog telemetry model as a preclinical predictor of QT interval prolongation in humans. Cardiovascular (hemodynamic and electrocardiographic) monitoring, via telemetry implants, was conducted for 2hr pre-dose and 24hr post-dosing with MOX with a toxicokinetic evaluation in a separate group of dogs. In both studies, MOX was administered orally by gavage in 0.5% methylcellulose at 0, 10, 30, and 100mg/kg. Inherent variability of the model was assessed with administration of 4 doses of vehicle (0.5% methylcellulose) alone in all 4 dogs to mimic a dose-escalation paradigm. QT was corrected for heart rate (QTc) using an individual animal correction (Miyazaki and Tagawa, 2002). MOX produced signifi cant dose-related increases in QTc at doses of 10 (Cmax = 7.0±0.5μM), 30 (Cmax = 20.4±1.8μM), and 100 (Cmax = 39.5±5.91μM) mg/kg with peak increases of 14 (6%), 27 (12%), and 45 (20%) msec, respectively (p≤0.05 vs. vehicle). QTc increases (3 to 6%) at 10mg/kg of MOX were comparable to QT/QTc increases (4.0±5.1%) in humans at a therapeutic dose (400mg, Cmax = 7.5±2.7μM) (Demolis et al., 2000). The small change in QTc (3%) at 10mg/kg of MOX was not due to the variability in QTc observed in dogs as no signifi cant QTc changes occurred on days 2, 3, and 4 in a study with vehicle alone. In conclusion, the dog telemetry model exhibits high sensitivity to detect small but signifi cant QT/QTc increases with MOX in the same range of therapeutic plasma concentrations attained in humans.