Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • New drugs are expected to undergo rigorous clinical electrocardiographic evaluation ('thorough QT/QTc study') during their early clinical development in order to determine any affect on cardiac repolarization. • The fluoroquinolone antibiotic moxifloxacin (400 mg) has been used as a positive comparator for thorough QT/QTc studies due to its QT prolongation (QTcF) of between 6 and 10 ms. • Positive comparators that are able to produce mean changes close to the regulatory guidelines of 5 ms, and which can be detected by the assay in use, would enable a more rigorous evaluation of the assay conditions used in evaluating new chemical entities. WHAT THIS STUDY ADDS • This thorough QT/QTc study directly compares the effects of two doses of levofloxacin and moxifloxacin on QTc in the same healthy subjects. • Mean QTc was prolonged in subjects receiving levofloxacin compared with placebo as determined by both individual and Fridericia's heart rate correction methods. • The largest time-matched differences in QTc for two doses of levofloxacin compared with placebo suggest the potential for using levofloxacin in more rigorous QT/QTc studies, providing a robust evaluation of the assay conditions used in determining potential effects on cardiac repolarization. • There is evidence to suggest that levofloxacin moderately increases heart rate in a dose-dependent fashion. AIMS: To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. METHODS: Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. RESULTS: Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. CONCLUSIONS: Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms.