Treatment with trastuzumab, an anti-human epidermal growth factor receptor type 2 humanized monoclonal antibody, has been associated with heart failure in certain cancer patients; however, the mechanism underlying trastuzumab-induced cardiac dysfunction remains unclear. The present study was conducted to clarify the cardiac effects of trastuzumab in cynomolgus monkeys which are commonly used as cross-reactive species in preclinical safety evaluation. Monkeys were treated with trastuzumab weekly for one month (5 dosed in total) to monkeys. At first and fifth doses for pressure-volume loop analysis, trastuzumab at 20 mg/kg/10 min, equivalent to the human therapeutic dose, was administered intravenously to isoflurane-anesthetized animals followed by 60 mg/kg/10 min at a 30-min interval. The other doses were fixed at 80 mg/kg/10 min under unanesthetized conditions. After the first dose, reduced heart rate, and decreases in maximal rate of fall of left ventricular pressure and prolonged time constant for isovolumic relaxation, which are predictors of drug-induced changes in lusitropy, were observed at 20 and 60 mg/kg. The changes after the fifth dose were comparable to those after the first dose, indicating trastuzumab didn't show exacerbation of cardiac function during the one-month trial. No significant changes in slope of preload recruitable stroke work, which is a load-independent inotropic parameter, were observed at either dose. In conclusion, trastuzumab induced little inotropic effect, but negative chronotropic or lusitropic effect in monkeys, which might be associated with impaired left ventricular diastolic function.

中文翻译：

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曲妥珠单抗在食蟹猴中诱导负性变时性和松弛性作用。

曲妥珠单抗（一种抗人表皮生长因子受体 2 型人源化单克隆抗体）治疗与某些癌症患者的心力衰竭有关；然而，曲妥珠单抗引起的心功能障碍的机制仍不清楚。本研究旨在阐明曲妥珠单抗对食蟹猴的心脏影响，食蟹猴通常被用作临床前安全性评估中的交叉反应物种。每周用曲妥珠单抗对猴子进行治疗，持续一个月（总共 5 剂）。在用于压力-容积环分析的第一和第五剂量中，曲妥珠单抗以 20 mg/kg/10 分钟（相当于人类治疗剂量）静脉内施用给异氟烷麻醉的动物，随后以 30-20 的剂量以 60 mg/kg/10 分钟施用。最小间隔。其他剂量在非麻醉条件下固定为 80 mg/kg/10 分钟。首次给药后，在 20 和 60 mg/kg 剂量下观察到心率降低、左心室压力最大下降速率降低和等容舒张时间常数延长，这些都是药物引起的松驰性变化的预测因素。第五次给药后的变化与第一次给药后的变化相当，表明曲妥珠单抗在一个月的试验中没有表现出心功能恶化。在任一剂量下均未观察到预负荷可复张冲程功的斜率发生显着变化，这是一个与负荷无关的正性肌力参数。总之，曲妥珠单抗在猴子中几乎没有引起正性肌力作用，但引起负变时或变舒作用，这可能与左心室舒张功能受损有关。