Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Japan.
Clinical Trial Center, Kitasato University Hospital, Sagamihara, Japan.
Pharm Stat. 2021 Mar;20(2):375-389. doi: 10.1002/pst.2083. Epub 2020 Dec 8.
The QTc interval of the electrocardiogram is a pharmacodynamic biomarker for drug-induced cardiac toxicity. The ICH E14 guideline Questions and Answers offer a solution for evaluating a concentration-QTc relationship in early clinical studies as an alternative to conducting a thorough QT/QTc study. We focused on covariance structures of QTc intervals on the baseline day and dosing day (two-day covariance structure,) and proposed a two-day QTc model to analyze a concentration-QTc relationship for placebo-controlled parallel phase 1 single ascending dose studies. The proposed two-day QTc model is based on a constrained longitudinal data analysis model and a mixed effects model, thus allowing various variance components to capture the two-day covariance structure. We also propose a one-day QTc model for the situation where no baseline day or only a pre-dose baseline is available and models for multiple ascending dose studies where concentration and QTc intervals are available over multiple days. A simulation study shows that the proposed models control the false negative rate for positive drugs and have both higher accuracy and power for negative drugs than existing models in a variety of settings for the two-day covariance structure. The proposed models will promote early and accurate evaluation of the cardiac safety of new drugs.
心电图的 QTc 间期是药物引起心脏毒性的药效学生物标志物。ICH E14 指南问答为评估早期临床研究中的浓度-QTc 关系提供了一种替代方法，即无需进行全面的 QT/QTc 研究。我们专注于基线日和给药日的 QTc 间隔的协方差结构（两天的协方差结构），并提出了一个两天的 QTc 模型来分析安慰剂对照平行 1 期单递增剂量研究的浓度-QTc 关系。所提出的两天 QTc 模型基于约束的纵向数据分析模型和混合效应模型，从而允许各种方差分量来捕获两天的协方差结构。我们还为没有基线日或只有给药前基线的情况提出了一天的 QTc 模型，以及在多天内有浓度和 QTc 间隔的多递增剂量研究的模型。一项模拟研究表明，在所提出的两天的协方差结构的各种设置下，与现有模型相比，所提出的模型对阳性药物控制假阴性率，对阴性药物具有更高的准确性和功效。所提出的模型将促进新药心脏安全性的早期和准确评估。
