Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models
Precise safety pharmacology studies of lapatinib for onco-cardiology assessed using in vivo canine models
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DOI：
10.1038/s41598-020-57601-x
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发表时间：
2020-01-20
影响因子：
4.6
通讯作者：
Cao, Xin
中科院分区：
文献类型：
--
作者：
Ando, Kentaro;Wada, Takeshi;Cao, Xin
癌症化疗改善了癌症患者的预后，导致大量且快速增加的癌症幸存者。“肿瘤心脏病学”或“心脏肿瘤学”是一门新学科，用于解决新开发的癌症药物的意外心脏副作用。拉帕替尼是一种抑制表皮生长因子受体和ErbB2的酪氨酸激酶抑制剂，已用于晚期或转移性乳腺癌的治疗。据报告，拉帕替尼可诱导心血管不良事件，包括QT间期延长和心力衰竭。然而，它们尚未被临床前研究预测。因此，需要建立一种新的方法来评估酪氨酸激酶诱导的不良反应。在这里，我们静脉注射拉帕替尼氟烷麻醉的狗，评价心脏血流动力学，电生理学和超声心动图的药理学安全性评估。我们对慢性房室传导阻滞比格犬静脉注射拉帕替尼，以评估其潜在的预防作用。拉帕替尼治疗浓度显著增加总外周血管阻力、QT、QTc、单相动作电位（MAP）（90（窦性）、MAP（90（CL 400））、有效不应期和心肌肌钙蛋白I（cTnI）血浆浓度，表明拉帕替尼延长心室复极而不诱导致死性室性心律失常。仔细监测血浆肌钙蛋白I浓度和心电图可能是支持性生物标志物，可预测拉帕替尼诱导的心血管不良事件的发生。
Cancer chemotherapies have improved prognosis in cancer patients, resulting in a large and rapidly increasing number of cancer survivors. "Onco-cardiology" or "cardio-oncology" is a new discipline for addressing the unanticipated cardiac side effects of newly developed cancer drugs. Lapatinib, a tyrosine kinase inhibitor suppressing the epidermal growth factor receptor and ErbB2, has been used in advanced or metastatic breast cancer treatment. Reportedly, lapatinib has induced cardiovascular adverse events including QT-interval prolongation and heart failure. However, they have not been predicted by preclinical studies. Hence, a new method to assess the tyrosine kinase inhibitor-induced adverse effects needs to be established. Here, we intravenously administered lapatinib to halothane-anaesthetised dogs, evaluating cardiohemodynamic, electrophysiological, and echocardiographic profiles for pharmacological safety assessments. We intravenously administered lapatinib to chronic atrioventricular block beagle dogs to assess its proarrhythmic potential. The therapeutic concentration of lapatinib significantly increased total peripheral vascular resistance, QT, QTc, monophasic action potential (MAP)(90(sinus),) MAP(90(CL400)), effective refractory period, and plasma concentration of cardiac troponin I (cTnI), suggesting that lapatinib prolonged the ventricular repolarization without inducing lethal ventricular arrhythmia. Careful monitoring of plasma cTnI concentration and an electrocardiogram could be supportive biomarkers, predicting the onset of lapatinib-induced cardiovascular adverse events.