Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Astellas Pharma Global Development, Northbrook, IL, USA.
J Pharmacokinet Pharmacodyn. 2018 Jun;45(3):383-397. doi: 10.1007/s10928-017-9558-5. Epub 2017 Dec 5.
The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.
国际协调理事会通过问答程序修订了 E14 指南，允许使用浓度-校正 QT（C-QTc）建模作为主要分析方法，以评估新药的 QT 间期延长风险。在早期的 1 期研究中，基于 C-QTc 建模进行精心设计和实施的 QTc 评估，可以替代某些药物的全面 QT 研究，以可靠地排除临床相关的 QTc 效应。本白皮书提供了如何使用早期临床药理学和全面 QT 研究中的 C-QTc 建模来规划和进行药物的明确 QTc 评估的建议。涵盖的主题包括：1 期研究中的重要研究设计特征；建模目标和方法；探索性图；预先指定的线性混合效应模型；模型开发和评估的一般原则；以及对模型分析计划和报告的期望。这些建议基于当前最佳建模实践、科学文献和作者的个人经验。随着药物开发过程中实施情况提供更多数据以及分析方法的进步，预计这些建议将不断发展。
