Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects

Abstract

Aims: The aims of this study were three-fold and were to (i) investigate the effect of food (fasted and fed state) on the degree of QT prolongation caused by moxifloxacin under the rigorous conditions of a TQT study, (ii) differentiate the effects on QTc that arise from changes in PK from those arising as a result of electrophysiological changes attributable to raised levels of C-peptide [11] offsetting in part the IKr blocking properties of moxifloxacin and (iii) characterize the QTc F profile of oral moxifloxacin (400 mg) in healthy Japanese volunteers compared with Caucasian subjects.

Methods: The study population consisted of 32 healthy non-smoking, Caucasian (n = 13) and Japanese (n = 19), male and female subjects, aged between 20-45 years with a body mass index of between 18 to 25 kg m(-2). Female volunteers were required to use an effective contraceptive method or be abstinent. Subjects with ECGs which were deemed unsuitable for evaluation in a TQT study were excluded. ECGs were recorded in triplicate with subsequent blinded manual adjudication of the automated interval measurements. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition.

Results: The results demonstrated a substantial change in the typical moxifloxacin effect on the ECG. The effect on ΔΔQTc in the fed state led to a significant delay and a modest reduction compared with the fasted state correcting both conditions with the corresponding placebo data. The largest QTc F change from baseline in the fed state was observed at 4 h with a peak value of 11.6 ms (two-sided 90% CI 9.1, 14.1). In comparison, the largest QTc F change observed in the fasted state was 14.4 ms (90% CI 11.9, 16.8) and occurred at 2.5 h post-dose. The PK of moxifloxacin were altered by food and this change was consistent with the observed QTc F change. In the fed state plasma concentrations of moxifloxacin were considerably and consistently lower in comparison with the fasted state, and this applied to both ethnicities. The concentration-effect analysis revealed that there was no change in slope and confirmed that the difference in this analysis was caused by a change in the PK profile of moxifloxacin. Comparisons of the moxifloxacin effect in the fed state compared with fasted placebo also revealed a pharmacodynamic effect whereby a meal appears to antagonize the effects of moxifloxacin on the lengths of the QTc interval.

Conclusions: Our findings demonstrate that the food effect by itself leads to a shortening of the QTc interval offsetting in part the effects of a 400 mg single dose of oral moxifloxacin. The typical moxifloxacin PK profile is also altered by food prior to dosing reducing the Cmax and delays the peak effects on QTc up to several hours thereby reducing the overall magnitude of the effect and delaying the peak QTc prolongation. The contribution of the two effects was clearly discernible. Given that moxifloxacin is sometimes given with food in TQT studies, consideration should be given to adequate baseline corrections and appropriate sampling time points. In this study the PK-PD relationship was similar for Japanese and Caucasian subjects in the fed and fasted conditions, thereby providing further evidence that the sensitivity to the QTc prolonging effects of fluoroquinolones was likely to be independent of ethnicity. The small differences observed between the two subpopulations were not statistically significant. However, future studies should give consideration to formal ethnic comparisons as a secondary outcome parameter as very little is known about the relationship between ethnicity and drug effects on cardiac repolarization.

Keywords: Japanese bridging; PK/PD; QTc prolongation; fed and fasted moxifloxacin; thorough QT study.

© 2013 The British Pharmacological Society.

Figures

Figure 1

Changes in QTcF after a 400 mg dose of moxifloxacin with and without food (n = 32). The time course relationship comparing the moxifloxacin effects with and without food (A). The direct effects of food on QTc are removed as food is also given in both treatment arms where it would have had the same effects on QTc. The PK data (Figure 2) shows a delay and reduction in absorption (B). The PK–PD relationship is displayed in (B) and demonstrates that the delayed and somewhat lower effect of moxifloxacin is entirely driven by the altered PK of the drug. The regression lines are derived from a linear mixed effects model with concentration as covariate, ethnicity and gender and their interactions with concentration as fixed effects and random intercept and slope by subject. The vertical lines give the 95% CI for the predicted effect at the geometric mean Cmax in the fed and fasted states respectively. , effect on QTcF (fed estimate); , effect on QTcF (fasted estimate); , female; , male; , fed; , fasted

Figure 2

Individual plasma concentrations of 400 mg moxifloxacin in fasted and fed state. The individual moxifloxacin concentrations, plotted by ethnicity and feeding status showing the delay in absorption when moxifloxacin is taken 10 min after finishing a carbohydrate rich breakfast. , moxifloxacin 400 mg fasted (Japanese); , moxifloxacin 400 mg + breakfast (Japanese); , moxifloxacin 400 mg fasted (Caucasian); , moxifloxacin 400 mg + breakfast (Caucasian)

Figure 3

Pharmacokinetic predicted effects of food, (fed and fasted) on the moxifloxacin effect on the QTcF interval. Time matched mean changes from placebo (fasting placebo was subtracted from fed moxifloxacin to reveal the PD contribution of food). The vertical bars give the predicted effect of moxifloxacin on ΔΔQTcF under a common model for the fed and fasted state for time points for which moxifloxacin concentrations were measured. The observed effect of moxifloxacin in the fasted state is the difference between the black and the blue curve. The combined effect of moxifloxacin plus a meal is shown by the red line. The effects match the vertical bars, i.e. the model predicts the mean effect over time. , moxifloxacin fasted; , moxifloxacin fed; , breakfast; , placebo.

Figure 4

ΔΔQTcF in fasted and fed state in healthy Japanese and Caucasian subjects. The difference between the two curves represents the effect of the moxifloxacin on QTcF in Japanese and Caucasian. A) shows the time course relationship in the fasting condition and B) after breakfast (fed). (A) , fasted Japanese; , fasted Caucasian; (B) fed Japanese; fed Caucasian

Figure 5

PK-ΔΔQTcF relationship (fed/fasted) for Japanese and Caucasian subjects. The PK–PD relationship by ethnicity: Japanese volunteers show a slightly steeper dose–response curve than Caucasian volunteers in the fasted state (A). However, this is reversed in the fed state (B). In this study, the sample size was small and the effect was likely to have been caused by random effect owing to the small sample size. , female; , male; , Japanese; , Caucasian