Differentiation of arrhythmia risk of the antibacterials moxifloxacin, erythromycin, and telithromycin based on analysis of monophasic action potential duration alternans and cardiac instability.
Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á-go-go-related gene (hERG) with IC20 concentrations of 31 microM (moxifloxacin), 21 microM (erythromycin), and 11 microM (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 microM). Erythromycin also increased MAPD at its highest free drug concentration (58 microM), but alternans occurred at a relatively lower therapeutic multiple (13.9 microM), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 microM). The relative risk at therapeutic concentrations is erythromycin>moxifloxacin>telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.
Wisialowski
Todd
T
Pfizer Global Research and Development, Eastern Point Rd., Building 274, Groton, CT 06340, USA.
Crimin
Kimberly
K
Engtrakul
Juntyma
J
O'Donnell
John
J
Fermini
Bernard
B
Fossa
Anthony A
AA
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001372:Aza Compounds / Q000633:toxicity*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000633:toxicity*; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D024841:Fluoroquinolones; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048628:Ketolides / Q000633:toxicity*; D000077266:Moxifloxacin; D011804:Quinolines / Q000633:toxicity*; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
D001372:Aza Compounds; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D048628:Ketolides; D011804:Quinolines; D004917:Erythromycin; C106791:telithromycin; D000077266:Moxifloxacin