Título / Title

EXPERIMENTAL INVESTIGATION AND CRITICAL ASSESSMENT OF A NOVEL ANTI-ANGIOGENIC DRUG - RAMUCIRUMAB - FOR RETINAL PHARMACOTHERAPY

Introdução / Purpose

The primary purpose of the study is to investigate the ocular and retinal safety of intravitreal (IVT) ramucirumab (Cyramza®) in animal model and cell culture model.

Material e Método / Methods

Sixteen chinchilla rabbits were divided in two groups and given IVT injection of 0.025 ml or 0.05 ml ramucirumab at 10 mg/ml in right eye (OD). In all groups, balanced salt solution (BSS) in left eye (OS) served as control. Animals were examined by fundoscopy, electroretinography (ERG) and optical coherence tomography (OCT). Blood serum and humor aqueous were obtained at baseline and 24 hours or seven days after for osmolarity evaluation. Animals were killed and both eyes (OU) were assessed by light microscopy or transmission electron microscopy (TEM). Human retinal cultured cells (ARPE-19) toxicity were assessed with MTT cell viability assays. A detailed and critical evaluation of advantages of novel anti-angiogenic drugs was performed after review of the medical literature.

Resultados / Results

All eyes were negative for cataract, hemorrhage or retinal detachment at 24 hours or seven days after procedures. No statistical alterations in ERG were recorded 24 hours or one week after both drug injection. OCT was normal in 24 hours and seven days after IVT injection. The baseline median serum, and aqueous osmolarity remained unchanged after 24 hours or seven days after ramucirumab. Histology and TEM showed no major anatomic signs of toxicity. There was a statistical significant diminish in ganglion cell number between the control and the eyes that received 0.05ml of ramucirumab. No significant cytotoxic effect was observed in ARPE-19 cells exposed to ramucirumab in the assessed concentrations.

Discussão e Conclusões / Conclusion

Ramucirumab may be safe for the retina after IVT injection. There was no functional damage detected, but the 0.05ml dose can cause a diminish in ganglion cell number after 7 days of the injection.

Palavras Chave

Pharmacokinetics, Ramucirumab, drug safety, monoclonal antibodies, angiogenesis, vascular endothelial growth factor, intravitreal injection