Nonclinical Safety, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110-1199, USA.
Int J Toxicol. 2010 May-Jun;29(3):259-67. doi: 10.1177/1091581810361527.
Trastuzumab is indicated for the treatment of patients with breast cancer overexpressing human epidermal growth factor 2 (HER2). Women with HER2-positive tumors have an increased risk of brain metastases. The blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain and CSF following standard intravenous administration. To evaluate the potential of effects on the central nervous system, a 4-week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0, 3, or 15 mg. No trastuzumab-related effects on body weight, clinical signs, neurological function, clinical pathology, or anatomic pathology were noted. The applied doses and CSF concentrations achieved in the current study exceeded those reported in patients after intrathecal administration. The results support future studies for further evaluation of intrathecal application of trastuzumab in patients with brain metastases in HER2-positive breast cancer.
曲妥珠单抗适用于治疗人表皮生长因子 2（HER2）过表达的乳腺癌患者。HER2 阳性肿瘤的女性发生脑转移的风险增加。血脑屏障和血脑脊液（CSF）屏障可能会阻止曲妥珠单抗在标准静脉给药后达到大脑和 CSF 中的适当浓度。为了评估对中枢神经系统的潜在影响，在剂量为 0、3 或 15 mg 的食蟹猴中进行了为期 4 周的每周鞘内给予曲妥珠单抗的毒理学研究。未观察到曲妥珠单抗相关的体重、临床症状、神经功能、临床病理学或解剖病理学变化。目前研究中达到的应用剂量和 CSF 浓度超过了报告的鞘内给予曲妥珠单抗后患者的浓度。这些结果支持进一步研究曲妥珠单抗鞘内应用于 HER2 阳性乳腺癌脑转移患者的研究。
