Bloomfield D M, Kost J T, Ghosh K, Hreniuk D, Hickey L A, Guitierrez M J, Gottesdiener K, Wagner J A
Department of Clinical Pharmacology, Merck Research Laboratories, Merck and Company, Rahway, New Jersey, USA.
Clin Pharmacol Ther. 2008 Oct;84(4):475-80. doi: 10.1038/clpt.2008.33.
A number of issues have remained unanswered in the design of "thorough QT"(TQT) studies. In this randomized, placebo-controlled, two-period crossover study in 20 healthy subjects, replicate electrocardiograms (ECGs) were recorded on a digital 12-lead Holter recorder, extracted in a core ECG laboratory, and interpreted manually by a cardiologist. The observed within-subject variability was slightly greater when time-matched baselines were employed than when predose baselines were employed, whereas the magnitude of the increase in QTc was similar for both. Moxifloxacin 400 mg was associated with an observed 7.5-12.5 ms increase in the mean placebo- and baseline-corrected QTc interval. A PK-QTc model estimated a 3.9 ms increase in the QTc interval for every 1,000 ng/ml increase in moxifloxacin concentration. The QTc increases associated with moxifloxacin support the appropriateness of its use as a positive control in TQT studies. This crossover study failed to justify the use of time-matched baselines rather than the less resource-intensive predose definition of baseline.
在“全面QT”（TQT）研究的设计中，仍有一些问题未得到解答。在这项针对20名健康受试者的随机、安慰剂对照、两阶段交叉研究中，在数字12导联动态心电图记录仪上记录重复心电图（ECG），在核心心电图实验室提取，并由心脏病专家进行人工解读。与采用给药前基线相比，采用时间匹配基线时观察到的受试者内变异性略大，而两者的QTc增加幅度相似。400毫克莫西沙星与观察到的平均安慰剂校正和基线校正QTc间期增加7.5 - 12.5毫秒相关。一个药代动力学- QTc模型估计，莫西沙星浓度每增加1000纳克/毫升，QTc间期增加3.9毫秒。与莫西沙星相关的QTc增加支持了其在TQT研究中作为阳性对照使用的合理性。这项交叉研究未能证明使用时间匹配基线而非资源消耗较少的给药前基线定义是合理的。
