ABSTRACT

The baseline selection in concentration-QTc (C-QTc) modeling is not well studied in the literature. Time-matched baseline and pre-dose baseline have been commonly used as a covariate in C-QTc modeling for parallel and crossover study, respectively. It has been showed that the C-QTc model using time-matched baseline has a low chance of showing assay sensitivity in parallel study. To better understand the impacts of baseline section in C-QTc, we examined the original and subsampled moxifloxacin and placebo data from more than 50 of TQT studies submitted to FDA with regard to assay sensitivity. Our analyses show that baseline selection (time-matched, pre-dose, average) has an impact on prediction from C-QTc modeling and the impact depends on study design (parallel, crossover). The impact to categorical table of ΔQTc is unlikely to alter the interpretation of the outlier category (ΔQTc>60) that corresponds to the regulatory concern. The results presented here can guide C-QTc study design as well as baseline selection in C-QTc modeling.

摘要

浓度-QTc (C-QTc) 建模中的基线选择在文献中没有得到很好的研究。时间匹配基线和给药前基线分别常用作平行和交叉研究的 C-QTc 建模的协变量。已经表明，使用时间匹配基线的 C-QTc 模型在平行研究中显示检测灵敏度的机会很低。为了更好地了解 C-QTc 中基线部分的影响，我们检查了来自提交给 FDA 的 50 多项 TQT 研究的原始和二次抽样莫西沙星和安慰剂数据，其中涉及测定灵敏度。我们的分析表明，基线选择（时间匹配、给药前、平均）对 C-QTc 建模的预测有影响，这种影响取决于研究设计（平行、交叉）。ΔQTc 对分类表的影响不太可能改变与监管关注相对应的异常值类别 (ΔQTc>60) 的解释。此处介绍的结果可以指导 C-QTc 研究设计以及 C-QTc 建模中的基线选择。