Vol.57 No.2 March 2009
Effect of single 500 mg iv. levofloxacin dose on QT interval in healthy subjects
1)Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, Japan
2)R&D Division, Daiichi Sankyo Company, Limited
3)Clinical Trial Center, Kitasato University East Hospital
Abstract
We conducted a placebo-controlled, single-blind, randomized, two-treatment, two-period crossover study to evaluate the effect of a single intravenous 500 mg levofloxacin dose on QT interval in 48 healthy Japanese men and women equally distributed across age (20-45 vs. 65-79 years) and gender strata. Subjects received either levofloxacin or saline in the first period, then reverse treatment in the second period. During each treatment period, standard 12-lead electrocardiogram(ECG) was recorded at 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours after the start of infusion. ECG was transmitted digitally to an ECG core laboratory, where trained readers blinded to subject information manually measured ECG parameters. Heart-rate-corrected QT intervals were calculated using the Fridericia (QTcF) and Bazett (QTcB) formulas and a nonlinear regression model with a study population-specific coefficient (QTcP=QT/RR0.410). Linear mixed models were used to estimate mean change in the QT interval from baseline (ΔQT/QTc) and between-treatment (levofloxacin-placebo) differences in changes (ΔΔQT/QTc), together with corresponding upper bounds of one-sided 95% confidence intervals. ΔQTcF at Tmax was 2.1 ms with levofloxacin and -1.3 ms with placebo. The ΔΔQTcF was 3.4 ms (upper bound of one-sided 95% confidence interval, 5.2 ms), generally considered associated with no risk of Torsades de Pointes. ΔΔQTcF was slightly greater in women and the elderly than in men and younger subjects but was less than 5 ms in all subgroups. Levofloxacin showed a very small effect on the QT interval, indicating that levofloxacin is very unlikely to cause Torsades de Pointes.
Key word
levofloxacin, QT interval
Received
October 31, 2008
Accepted
December 12, 2008
Jpn. J. Chemother. 57 (2): 106-114, 2009
