Yan Lihan K, Zhang Joanne, Ng Moh Jee, Dang Qianyu
Division of Biometrics VI, Office of Biostatistics/Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
J Biopharm Stat. 2010 May;20(3):497-507. doi: 10.1080/10543400903581945.
Moxifloxacin has been the most commonly used positive control in "thorough" QTc (TQT) studies. In a TQT study, the assay sensitivity is often considered to be established if the baseline corrected mean difference in QTc between moxifloxacin and placebo is greater than 5 ms in common practice at one or more prespecified time points and the observed moxifloxacin induced QTc effect over time follows the proper pharmacokinetics profile. To better understand the statistical characteristics of moxifloxacin-induced QTc prolongation and to provide guidance for future studies, 20 TQT studies that involved moxifloxacin have been evaluated. We study the QTc profile of the baseline adjusted mean difference in QTc between moxifloxacin and placebo over time. Zhang (2008) proposed that the moxifloxacin induced QTc effect can be evaluated between 1 and 4 h after a single dose (400 mg) administration near the time (T(max)) of peak concentration instead of all time points (typically 9-12 time points) at which QT was measured for the study drug evaluation. After evaluating 20 TQT studies, we confirm that the maximum moxifloxacin effect occurs in the time window between 1 and 4 h post dose. We also investigate the variability of the data as well as correlations between time points and between regimens. These findings and results can be used as a reference for future studies.
莫西沙星一直是“全面”的QTc（TQT）研究中最常用的阳性对照药。在一项TQT研究中，如果在一个或多个预先指定的时间点，莫西沙星与安慰剂之间的基线校正QTc平均差异在常规情况下大于5毫秒，并且观察到的莫西沙星诱导的QTc效应随时间的变化遵循适当的药代动力学特征，那么通常认为该检测方法具有敏感性。为了更好地了解莫西沙星诱导的QTc延长的统计特征，并为未来的研究提供指导，我们评估了20项涉及莫西沙星的TQT研究。我们研究了莫西沙星与安慰剂之间的基线校正QTc平均差异随时间的QTc变化情况。Zhang（2008年）提出，莫西沙星诱导的QTc效应可以在单次给药（400毫克）后1至4小时内，在接近峰浓度时间（T(max)）时进行评估，而不是在研究药物评估中测量QT的所有时间点（通常为9至12个时间点）进行评估。在评估了20项TQT研究后，我们确认莫西沙星的最大效应出现在给药后1至4小时的时间窗口内。我们还研究了数据的变异性以及时间点之间和给药方案之间的相关性。这些发现和结果可作为未来研究的参考。
