Preclinical assessment of intravitreal ramucirumab: in vitro and in vivo safety profile

International Journal of Retina and Vitreous

卷:6

Raquel Leão Neves¹  Nilana Meza Tenório de Barros¹  Cristiane Damas Gil²  Arthur Gustavo Fernandes³  Carsten Helmut Meyer³  Michel Eid Farah³  Sung Eun Song Watanabe³  Jarbas Emílio de Moraes Neto³  Eduardo Buchele Rodrigues³  Felipe Pereira³ 

[1] Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP);

[2] Departamento de Morfologia E Genética, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP);

[3] Departamento de Oftalmologia E Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP);

关键词: Anti-VEGF;    Ramucirumab;    Safety;    Experimental;    Intravitreal injection;   

DOI  :  10.1186/s40942-020-00243-y

来源: DOAJ

【 摘 要 】

Abstract Background Anti-angiogenic drugs remain the mainstay therapy for several vascular retinal pathologies. The repurposing of approved anti-angiogenic drugs for use in ophthalmology can increase therapeutic options and reduce costs. The purpose of this study was to investigate the ocular safety profile of intravitreal (IVT) ramucirumab, an approved anti-vascular endothelial growth factor molecule for systemic treatment, using cell culture and animal models. Methods The cytotoxicity of ramucirumab at different concentrations was evaluated in human retinal pigment epithelial cells (ARPE-19) using the MTT assay. In addition, 250 or 500 µg of ramucirumab or vehicle was injected in the eye of 16 chinchilla rabbits. The eyes were evaluated by ophthalmoscopy, electroretinography, spectral-domain optical coherence tomography (SD-OCT) and by light and transmission electron microscopy. Results Electroretinography or SD-OCT did not detect functional or morphological alterations at 24 h or one week after injection. Light and transmission electron microscopy confirmed the absence of major signs of toxicity, although we found a statistically significant reduction in ganglion cell number between the controls and the eyes that received 500 µg of ramucirumab after 7 days. Compared to lower concentrations, 500 µg of ramucirumab caused reduction in cell viability and changes in morphology in ARPE-19 cells. Compared to the baseline, ocular and serum osmolarity showed no difference after IVT injection at all timepoints. Conclusion In conclusion, IVT injection of ramucirumab in rabbits is safe and does not cause functional damage to the retina. At the lower dose tested in vivo (250 µg), the morphology and ultrastructural anatomy were normal at 24 h and 1 week after the injection. However, the 500 µg dose can cause a decrease in ganglion cell number seven days after the injection.

【 授权许可】

Unknown