QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome.
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.
Chen
Xian
X
Department of Safety Pharmacology, Worldwide Safety Sciences, Groton-New London Laboratories, Groton, CT 06340, USA.
Cass
Jessica D
JD
Bradley
Jenifer A
JA
Dahm
Corinn M
CM
Sun
Zhuoqian
Z
Kadyszewski
Edmund
E
Engwall
Michael J
MJ
Zhou
Jun
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001372:Aza Compounds / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D000077266:Moxifloxacin; D010627:Phenethylamines / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D011804:Quinolines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D013686:Telemetry / Q000379:methods; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D001372:Aza Compounds; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D010627:Phenethylamines; D024661:Potassium Channels, Inwardly Rectifying; D011804:Quinolines; D013449:Sulfonamides; C063533:dofetilide; D000077266:Moxifloxacin