Taubel Jorg, Ferber Georg, Lorch Ulrike, Batchvarov Velislav, Savelieva Irina, Camm A John
Richmond Pharmacology Ltd, London, UK.
Br J Clin Pharmacol. 2014 Jan;77(1):170-9. doi: 10.1111/bcp.12168.
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.
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.
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.
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.
本研究的目的有三个，即（i）在TQT研究的严格条件下，研究食物（禁食和进食状态）对莫西沙星引起的QT延长程度的影响；（ii）区分QTc变化中由药代动力学变化引起的部分与因C肽水平升高导致的电生理变化引起的部分，C肽水平升高部分抵消了莫西沙星对IKr的阻断作用；（iii）比较健康日本志愿者与白种人受试者口服莫西沙星（400mg）后的QTcF特征。
研究人群包括32名健康的非吸烟受试者，其中白种人（n = 13）和日本人（n = 19），男女皆有，年龄在20 - 45岁之间，体重指数在18至25kg·m⁻²之间。女性志愿者需采用有效的避孕方法或禁欲。排除心电图被认为不适合在TQT研究中评估的受试者。心电图记录三次，随后对自动测量的间期进行盲法人工判定。安慰剂组的心电图在禁食和进食状态下各记录两次。
结果表明莫西沙星对心电图的典型效应有显著变化。与禁食状态相比，进食状态下对ΔΔQTc的影响导致显著延迟且有适度降低，两种状态均用相应安慰剂数据进行校正。进食状态下从基线观察到的最大QTcF变化在4小时出现，峰值为11.6ms（双侧90%CI 9.1，14.1）。相比之下，禁食状态下观察到的最大QTcF变化为14.4ms（90%CI 11.9，16.8），出现在给药后2.5小时。食物改变了莫西沙星的药代动力学，这种变化与观察到的QTcF变化一致。在进食状态下，莫西沙星的血浆浓度与禁食状态相比显著且持续较低，两种族均如此。浓度 - 效应分析表明斜率无变化，并证实该分析中的差异是由莫西沙星药代动力学特征的变化引起的。进食状态与禁食安慰剂状态下莫西沙星效应的比较还揭示了一种药效学效应，即进餐似乎拮抗了莫西沙星对QTc间期长度的影响。
我们的研究结果表明，食物效应本身导致QTc间期缩短，部分抵消了400mg单剂量口服莫西沙星的效应。给药前食物也改变了莫西沙星的典型药代动力学特征，降低了Cmax并将对QTc的峰值效应延迟数小时，从而降低了总体效应幅度并延迟了QTc延长的峰值。两种效应的贡献清晰可辨。鉴于在TQT研究中莫西沙星有时与食物一起给药，应考虑进行充分的基线校正和合适的采样时间点。在本研究中，进食和禁食条件下日本受试者和白种人受试者的药代动力学 - 药效学关系相似，从而进一步证明对氟喹诺酮类药物QTc延长效应的敏感性可能与种族无关。两个亚组之间观察到的微小差异无统计学意义。然而，未来的研究应考虑将正式的种族比较作为次要结果参数，因为关于种族与药物对心脏复极化影响之间的关系知之甚少。
