QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome
| Autor: | Chen, Xian, Cass, Jessica D, Bradley, Jenifer A, Dahm, Corinn M, Sun, Zhuoqian, Kadyszewski, Edmund, Engwall, Michael J, Zhou, Jun |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Male
Moxifloxacin Drug Evaluation Preclinical Action Potentials Cell Line Electrocardiography Dogs Anti-Infective Agents Phenethylamines Animals Humans Telemetry Potassium Channels Inwardly Rectifying Aza Compounds Sulfonamides Dose-Response Relationship Drug Arrhythmias Cardiac Ether-A-Go-Go Potassium Channels Disease Models Animal Long QT Syndrome Treatment Outcome Area Under Curve Papers Quinolines Female Rabbits Fluoroquinolones |
| Popis: | Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study, we investigated effects of moxifloxacin on the hERG current in HEK-293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model. Moxifloxacin inhibited the hERG current with an IC50 of 35.7 microM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg(-1), with mean serum Cmax of 8.52 and 22.3 microg ml(-1), respectively. In the wedge preparation, moxifloxacin produced a concentration-dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after-depolarizations were observed in one of five experiments at 30 microM and five of five experiments at 100 microM. The arrhythmogenic potential was also concentration-dependent, and 100 microM ( approximately 18-fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP). Our data indicated a good correlation among the concentration-response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well-behaved pharmacokinetic profile and other dose-limiting effects. |
| Databáze: | OpenAIRE |
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