Cardiovascular monkey telemetry: Sensitivity to detect QT interval prolongation

Introduction: 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...

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Bibliographic Details
Published in:	Journal of pharmacological and toxicological methods Vol. 54; no. 2; pp. 150 - 158
Main Authors:	Chaves, A.A., Keller, W.J., O'Sullivan, S., Williams, M.A., Fitzgerald, L.E., McPherson, H.E., Goykhman, D., Ward, P.D., Hoe, C.M., Mixson, L., Briscoe, R.J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-09-2006
Subjects:	Algorithms Animals Anti-Infective Agents - pharmacokinetics Anti-Infective Agents - toxicity Aza Compounds - pharmacokinetics Aza Compounds - toxicity Blood Pressure - drug effects Dose-Response Relationship, Drug Electrocardiography - drug effects Electrodes, Implanted Excipients Fluoroquinolones Heart Rate - drug effects Hemodynamics - physiology Long QT Syndrome - chemically induced Long QT Syndrome - diagnosis Long QT Syndrome - physiopathology Macaca mulatta Male Methods Methylcellulose Moxifloxacin QT interval Quinolines - pharmacokinetics Quinolines - toxicity Rhesus monkeys Sensitivity Telemetry QT interval Sensitivity Moxifloxacin Telemetry Methods Rhesus monkeys
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Summary:	Introduction: 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 monkey telemetry 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), with a toxicokinetic (TK) evaluation in a separate group of monkeys. In both studies, MOX was administered orally by gavage in 0.5% methylcellulose at 0, 10, 30, 100, 175 mg/kg. Each monkey received all 5 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle alone for 4 days in all 4 monkeys (0.5% methylcellulose in deionized water). Results: MOX had no significant effect on mean arterial pressure, heart rate, PR or QRS intervals. MOX produced significant dose-related increases in QTc at doses of 30 ( C max = 5.5 ± 0.6 μM), 100 ( C max = 16.5 ± 1.6 μM), and 175 ( C max = 17.3 ± 0.7 μM) mg/kg with peak increases of 22 (8%), 27 (10%), and 47 (18%) ms, respectively ( p ≤ 0.05; compared to vehicle). Discussion: In conclusion, we have developed a reproducible, sensitive and reliable primate telemetry model in rhesus monkeys, which exhibits low inherent intra-animal variability and high sensitivity to detect small but significant increases in QT/QT c interval (∼ 4%) with MOX in the same range of therapeutic plasma concentrations attained in humans. Therefore, the primate telemetry model should be considered an important preclinical predictor of QT prolongation of novel human pharmaceuticals.
ISSN:	1056-8719 1873-488X
DOI:	10.1016/j.vascn.2006.03.004