Clinical Pharmacology and Pharmacometrics, AbbVie Inc, North Chicago, Illinois, USA.
Clin Pharmacol Ther. 2018 May;103(5):836-842. doi: 10.1002/cpt.804. Epub 2017 Sep 25.
Exposure-response analyses of QT data from early-stage clinical studies represent a valuable tool to assess the QT prolongation potential for drugs in development in lieu of standalone thorough QT (TQT) studies. However, demonstrating adequate electrocardiogram assay sensitivity can be challenging in the absence of a positive pharmacological control. Upadacitinib is a Janus kinase 1 inhibitor currently being evaluated in phase III rheumatoid arthritis trials. Exposure-response analyses to evaluate the QT prolongation potential for upadacitinib from phase I trials and the utility of the effect of food on QTcF to demonstrate ECG assay sensitivity are presented. The analyses demonstrated no effect of upadacitinib on QT interval and confirmed the sensitivity of the ECG assay to detect the small QT shortening effect caused by food. Lack of bias from manual ECG adjudication was also demonstrated. These analyses supported requesting a waiver for the regulatory requirement for a dedicated thorough QT study for upadacitinib.
在缺乏阳性药理学对照的情况下，早期临床研究中的 QT 数据的暴露-反应分析代表了一种评估药物开发中 QT 延长潜力的有价值工具。然而，如果没有充分的检测手段，证明心电图检测方法的灵敏度可能是一项挑战。Upadacitinib 是一种正在进行 III 期类风湿关节炎临床试验的 Janus 激酶 1 抑制剂。本文介绍了评估 Upadacitinib 的 QT 延长潜力的 I 期临床试验中的暴露-反应分析，以及食物对 QTcF 的影响在证明 ECG 检测方法灵敏度方面的作用。分析结果表明 Upadacitinib 对 QT 间期没有影响，并证实了心电图检测方法对检测由食物引起的 QT 缩短的小效应的灵敏度。也证明了人工心电图校正没有偏差。这些分析结果支持请求豁免 Upadacitinib 的专用全面 QT 研究的监管要求。
