Data Sheet 1_Modelling of clinical TQT studies outcomes from preclinical cardiovascular safety pharmacology studies using the one-step QTc model.pdf

IntroductionRetrospective translational analyses have shown a high rate of false negatives between clinical thorough QT studies (TQT) and preclinical cardiovascular safety pharmacology studies. The aim of this work was to model the results of clinical TQT studies from cardiovascular safety pharmacology studies conducted on a large set of reference drugs in beagle dogs by implanted telemetry.
MethodsAll preclinical studies were based on a standard four-animal crossover design comparing the vehicle to the reference drug. The model used was based on the one-step QTc correction model. This model was adapted in order to apply the same statistical method in preclinical studies as in clinical trials.
ResultsThe sensitivity of the model made it possible to detect QTc prolongation of at least 5 ms with all reference hERG blockers known to cause QT prolongation in humans. Modelling of moxifloxacin (10 mg/kg, po) effects was in agreement with data published from clinical TQT studies with moxifloxacin 400 mg showing a QTc prolongation greater than 5 ms between 1 and 4 hours post-dose. This study shows a noticeable reduction in the risk of false negatives with several references drugs associated with a phenomenon of concealed QTc prolongation. Moreover, several reference drugs did change the slope of the QT/HR slope justifying the principles of the one-step QTc model.
ConclusionModelling results of TQT studies with the one-step QTc model for applying the same statistical approach as in the clinic can improve the translational value of preclinical cardiovascular safety pharmacology studies and reduce the risk of false negatives.

引言
回顾性转化分析显示，临床全面QT研究（clinical thorough QT studies, TQT）与临床前心血管安全药理研究之间存在较高的假阴性率。本研究旨在通过植入式遥测技术，基于比格犬的大量参考药物心血管安全药理研究数据，构建临床TQT研究结果的预测模型。

方法
所有临床前研究均采用标准四动物交叉设计，以赋形剂为对照与参考药物进行比较。本研究采用一步法QTc校正模型（one-step QTc correction model），并对其进行适配调整，以使临床前研究与临床试验采用统一的统计分析方法。

结果
该模型的灵敏度可检出所有已知可导致人类QT间期延长的参考hERG阻滞剂（hERG blockers）至少5ms的QTc间期延长。针对莫西沙星（10 mg/kg，口服）作用的建模结果，与临床TQT研究中莫西沙星400mg剂量下给药后1~4小时QTc间期延长超过5ms的已发表数据一致。本研究表明，对于多种存在隐匿性QTc间期延长现象的参考药物，假阴性风险可显著降低。此外，多种参考药物可改变QT/HR斜率，这印证了一步法QTc校正模型的原理。

结论
采用与临床研究一致的统计方法，通过一步法QTc校正模型对TQT研究结果进行建模，可提升临床前心血管安全药理研究的转化价值，并降低假阴性风险。