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

Abstract

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.

Figure 1

Summary of study design – a randomized, placebo-controlled, double-blind, double dummy, 4 × 4 crossover study

Figure 3

Largest time-matched difference from placebo in QTc: (QTcI and QTcF). QTcI (); QTcF ()

Figure 2

Mean QTcI change from baseline against time for moxifloxacin 400 mg, levofloxacin 1000 mg and levofloxacin 1500 mg. Lev 1000 mg (); Lev 1500 mg (); Moxi 400 mg ()

Figure 4

Heart rate change from baseline against plasma concentration for moxifloxacin 400 mg, levofloxacin 1000 mg and levofloxacin 1500 mg. Lev 1000 mg (); Lev 1500 mg (); Moxi 400 mg ()

Figure 5

QTcI change from baseline against plasma concentration for moxifloxacin 400 mg, levofloxacin 1000 mg and levofloxacin 1500 mg. Lev 1000 mg (); Lev 1500 mg (); Moxi 400 mg ()