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

BackgroundAnti-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.MethodsThe 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 mu g 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.ResultsElectroretinography 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 mu g of ramucirumab after 7 days. Compared to lower concentrations, 500 mu g 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.ConclusionIn 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 mu g), the morphology and ultrastructural anatomy were normal at 24 h and 1 week after the injection. However, the 500 mu g dose can cause a decrease in ganglion cell number seven days after the injection.