Population Pharmacokinetic and Concentration-QTc Models for Moxifloxacin: Pooled Analysis of 20 Thorough QT Studies
Population Pharmacokinetic and Concentration-QTc Models for Moxifloxacin: Pooled Analysis of 20 Thorough QT Studies
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DOI：
10.1177/0091270010381498
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发表时间：
2011-08-01
影响因子：
2.9
通讯作者：
Garnett, Christine E.
中科院分区：
文献类型：
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作者：
Florian, Jeffry A.;Tornoe, Christoffer W.;Garnett, Christine E.
为了加深我们对影响口服莫西沙星在全面 QT 研究中性能的重要受试者特征和设计变量的理解，通过汇集 20 项研究的数据开发了群体药代动力学和浓度 QTc 模型。具有一级消除的单室模型描述了药代动力学。使用 8 个运输隔间对吸收延迟进行建模。口腔清除率、表观分布容积、一级吸收速率常数和平均通过时间的平均（95%置信区间）值分别为11.7（11.5-11.9）L/h、147（144-150）L、1.9（1.7-2.1）1/h和0.3（0.28-0.34）小时。过度封装莫西沙星片剂使平均通过时间增加了 138%，并将达到最大浓度的时间延迟了 0.5 小时，但对总体暴露的影响很小。与食物同服使吸收率常数降低 27%。与男性相比，女性的莫西沙星暴露量更高，这是因为体重较低。线性模型描述了浓度-QTc 关系，平均斜率为每 μg/mL 莫西沙星 3.1 (2.8-3.3) 毫秒。个别研究的平均斜率范围为每μg/mL 1.6 至4.8 毫秒。莫西沙星血浆浓度和 QTc 之间的滞后是适度的，并且合并这种延迟不会导致不同的斜率（3.3 毫秒/μg/mL）。男性和女性之间或种族类别之间的坡度估计值没有差异。
To increase our understanding of important subject characteristics and design variables affecting the performance of oral moxifloxacin in thorough QT studies, population pharmacokinetic and concentration-QTc models were developed by pooling data from 20 studies. A 1-compartment model with first-order elimination described the pharmacokinetics. Absorption delay was modeled using 8 transit compartments. Mean (95% confidence interval) values for oral clearance, apparent volume of distribution, the first-order absorption rate constant, and mean transit time were 11.7 (11.5-11.9) L/h, 147 (144-150) L, 1.9 (1.7-2.1) 1/h, and 0.3 (0.28-0.34) hours, respectively. Overencapsulating the moxifloxacin tablet increased mean transit time by 138% and delayed time to maximum concentration by 0.5 hours but had a minimal effect on overall exposure. Administration with food decreased absorption rate constant by 27%. Women had higher moxifloxacin exposure compared with men, which was explained by lower body weights. A linear model described the concentration-QTc relationship with a mean slope of 3.1 (2.8-3.3) milliseconds per mu g/mL moxifloxacin. Mean slopes for individual studies ranged from 1.6 to 4.8 milliseconds per mu g/mL. Hysteresis between moxifloxacin plasma concentrations and QTc was modest, and incorporating this delay did not result in a different slope (3.3 milliseconds per mu g/mL). There were no differences in slope estimates between men and women or among race categories.