Abstract：
BACKGROUND: Nonclinical evaluation of the cardiovascular effects of novel chemical or biological entities (NCE, NBEs) is crucial for supporting first-in-human clinical trials. One important aspect of these evaluations is the assessment of potential QT/QTc prolongation risk, as drug-induced QT prolongation can have catastrophic effects. The recent publication of E14/S7B Q&As allows for the situational incorporation of nonclinical QTc data as part of an integrated risk assessment for a Thorough QT (TQT) waiver application provided certain best practice criteria are met. Recent publications provided detailed characterization of nonclinical QTc telemetry data collected from the commonly used Latin square study design.
METHODS: To understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design.
RESULTS: The data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment.
CONCLUSIONS: These findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications.
METHODS: To understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design.
RESULTS: The data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment.
CONCLUSIONS: These findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications.
摘要：
背景：对新型化学或生物学实体的心血管作用的非临床评估（NCE，NBEs）对于支持首次人体临床试验至关重要。这些评估的一个重要方面是评估潜在的QT/QTc延长风险，因为药物诱导的QT延长可能会产生灾难性的影响。E14/S7BQ&A的最新出版物允许将非临床QTc数据作为全面QT（TQT）豁免申请的综合风险评估的一部分，前提是满足某些最佳实践标准。最近的出版物提供了从常用的拉丁方研究设计中收集的非临床QTc遥测数据的详细表征。
方法：为了了解替代遥测研究设计的数据是否足以作为E14/S7B综合风险评估的一部分，我们报告了递增剂量遥测设计在确定QTc延长风险临床风险方面的性能和翻译敏感性.
结果：数据显示动物体内QTci间隔的低变异性，这表明研究环境得到了良好的控制，并且在整个给药日中对不受控制的影响的关注有限。n=4个受试者的递增剂量设计的历史研究差异，通过最小显著差异(LSD)和均方根误差(RMSE)值测量，足够低，可以检测到+10ms的QTci间隔变化，QTci间期变化的中位数最小可检测差异（MDD）<10ms。此外，浓度-QTci（C-QTci）评估以确定已知hERG抑制剂的+10msQTci增加与E14/S7B培训材料中列出的临床CC值相当，支持在E14/S7B综合风险评估中使用递增剂量设计。
结论：这些研究结果表明，递增剂量设计可以成为非临床评估QT/QTc延长风险和支持TQT豁免应用的有价值的工具。
方法：为了了解替代遥测研究设计的数据是否足以作为E14/S7B综合风险评估的一部分，我们报告了递增剂量遥测设计在确定QTc延长风险临床风险方面的性能和翻译敏感性.
结果：数据显示动物体内QTci间隔的低变异性，这表明研究环境得到了良好的控制，并且在整个给药日中对不受控制的影响的关注有限。n=4个受试者的递增剂量设计的历史研究差异，通过最小显著差异(LSD)和均方根误差(RMSE)值测量，足够低，可以检测到+10ms的QTci间隔变化，QTci间期变化的中位数最小可检测差异（MDD）<10ms。此外，浓度-QTci（C-QTci）评估以确定已知hERG抑制剂的+10msQTci增加与E14/S7B培训材料中列出的临床CC值相当，支持在E14/S7B综合风险评估中使用递增剂量设计。
结论：这些研究结果表明，递增剂量设计可以成为非临床评估QT/QTc延长风险和支持TQT豁免应用的有价值的工具。
