ru-66647 and Arrhythmias--Cardiac

The pharmacokinetic profiles of single and repeated oral doses of telithromycin 800 mg/day were compared in patients with hepatic impairment and healthy subjects in two open-label, non-randomized, parallel-group, multicentre studies. The maximal plasma concentrations (Cmax) and the area under the plasma concentration-time (AUC) curves for telithromycin were similar in hepatically impaired patients and healthy subjects in the single- and repeated-dose studies. The extent of formation of RU 76363, the major circulating metabolite of telithromycin, was decreased following single and repeated doses in patients with hepatic impairment compared with healthy subjects. In the single-dose study, the Cmax of RU 76363 was 2-fold lower (P<0.01) and the initial elimination half-life (t(1/2lambda1)) was 44% higher (P<0.01). The Cmax and AUC from 0 to 24 h post-dose were approximately 50% lower on Day 1 (P< or =0.01) and Day 7 (P< or =0.001) in the repeated-dose study. The terminal elimination half-life (t(1/2lambdaz)) of telithromycin was 1.4-fold higher (P<0.001) in the hepatically impaired patients compared with the healthy subjects in the single-dose study. However, t(1/2lambda1) and t(1/2lambdaz) were similar after repeated doses in both populations, suggesting that the decrease in formation of RU 76363 is compensated by an increase in clearance via other pathways. Telithromycin 800 mg was well tolerated in both populations. In conclusion, a once-daily dose of telithromycin is well tolerated in patients with hepatic impairment. Exposure to telithromycin was comparable in patients with hepatic impairment and healthy subjects and thus, no dosage adjustment is required in this patient group providing renal function is not severely impaired.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Arrhythmias, Cardiac; Drug Tolerance; Female; Half-Life; Humans; Ketolides; Liver Diseases; Macrolides; Male; Middle Aged; Safety

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.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Aza Compounds; Cell Line; Dose-Response Relationship, Drug; Erythromycin; Ether-A-Go-Go Potassium Channels; Fluoroquinolones; Guinea Pigs; Heart Rate; Humans; Ketolides; Moxifloxacin; Quinolines; Risk Factors; Torsades de Pointes