Abstract：
The ICH E14/S7B Q&As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the in vivo non-rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously evaluated by Darpo et al. (2015) in humans. The sensitivity of the assay to detect QTc increases was determined, and exposure-response analysis was performed, as done in clinical practice. By-timepoint analysis showed QTc prolongation induced by moxifloxacin, dofetilide, dolasetron, ondansetron, and quinine within human relevant plasma exposures ranges. Moreover, a hysteresis was observed for quinine. As expected, levocetirizine showed no statistically significant effect on QTc across a range of exposure, well exceeding the therapeutic Cmax. Power analyses confirmed the study ability to detect statistically significant QTc changes of less than 10 milliseconds with 80% probability, even with a sample size as low as n = 4 animals. Finally, concentration-QTc modeling enabled to predict the minimal plasma concentration needed to detect a 10 milliseconds QTc prolongation, including for quinine. The comparison with clinical available data supported the relevance of dogs under these experimental conditions as a robust translational predictor of drug-induced QTc prolongation in humans as a key pillar of the integrated risk assessment.
摘要：
ICHE14/S7BQ&A强调了有关设计的最佳实践的必要性，执行，分析,解释,并报告体内非啮齿动物QT测定作为综合风险评估的组成部分，以可能支持TQT豁免或替代。我们进行了一项狗遥测研究，以评估Darpo等人先前评估的六种参考化合物（五种阳性和一种阴性）对QTc的影响。（2015）在人类。确定了检测QTc增加的测定法的灵敏度，并进行了暴露反应分析，正如在临床实践中所做的那样。通过时间点分析显示莫西沙星诱导QTc延长，多非利特,dolasetron,昂丹司琼,和奎宁在人体相关血浆暴露范围内。此外，观察到奎宁的滞后现象。不出所料,左西替利嗪在一定范围内对QTc无统计学意义，远远超过治疗Cmax。功率分析证实了研究能力，以80％的概率检测小于10毫秒的统计显着QTc变化，即使样本量低至n=4只动物。最后,浓度-QTc模型能够预测检测10毫秒QTc延长所需的最小血浆浓度，包括奎宁。与临床可用数据的比较支持狗在这些实验条件下作为药物诱导的人类QTc延长的强大的翻译预测因子作为综合风险评估的关键支柱的相关性。
