Charles River Laboratories, Laval, Quebec, Canada.
70354Faculté de médecine vétérinaire, Université de Montréal, Québec, Canada.
Int J Toxicol. 2020 Nov/Dec;39(6):530-541. doi: 10.1177/1091581820954865. Epub 2020 Oct 16.
Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals.
Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects.
Covariate adjusted QT (slope -12.57 ms/°C) and JTpca (-14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca.
Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.
校正的 QT（QTc）间期是一种重要的致心律失常风险生物标志物，但最近的数据已经确定了其使用的局限性。J 到 T 峰（JTp）间期是评估药物致心律失常风险的替代生物标志物。本研究旨在评估在协变量校正 QT（QTca）、协变量校正 JTp（JTpca）和 T 峰到 T 末（Tpeca）间期方面，空间幅度导联和 DII 心电图（ECG）导联以及常见 ECG 混杂因素（即应激和体温变化）对药物的药理学作用。
将比格犬暴露于体温过高（42°C）或过低（33°C）条件下，或给予肾上腺素以评估对心率校正的 QTca、JTpca 和 Tpeca 间期的混杂影响。给予多非利特（0.1、0.3、1.0mg/kg）、雷诺嗪（100、140、200mg/kg）和维拉帕米（7、15、30、43、62.5mg/kg）以评估药物的药理学作用。
协变量校正 QT（斜率-12.57ms/°C）和 JTpca（-14.79ms/°C）与体温呈负相关，但 Tpeca 受影响最小。肾上腺素与 QTca 和 JTpca 缩短有关，这可能与心动过速时校正不足有关，而 Tpeca 则观察到最小的影响。雷诺嗪给药后心电图无明显变化。维拉帕米降低 QTca 和 JTpca 间期并增加 Tpeca，而多非利特增加 QTca 和 JTpca 间期，但对 Tpeca 的影响不一致。
结果突出了非临床研究中 QTc 间期以及 JTpca 和 Tpeca 间期的潜在混杂因素。这些潜在的混杂效应可能与从比格犬非临床药物安全性研究中获得的 ECG 数据的解释有关。
