Retinal Toxicity of Intravitreal Injection of Ziv-Aflibercept in Albino Rabbits

Abstract

PurposeTo evaluate retinal toxicity of ziv-aflibercept, a drug that had been approved for use for patients with colon cancer.MethodsTwenty-two albino rabbits were injected intravitreally with 0.1 mL of ziv-aflibercept solution into the experimental eye and 0.1-mL saline into the control eye. Twelve were used for electroretinogram (ERG) at 4-weeks follow-up. An additional 10 rabbits were used for testing penetration of ziv-aflibercept into the retina during follow-up. The visual-evoked potential (VEP) was recorded after 4 weeks of ERG follow-up. Glial fibrillary acidic protein (GFAP) immunocytochemistry and retinal histology were performed after the termination of the follow-up period.ResultsThe ERG responses of the experimental eyes did not show signs of permanent functional damage. The VEP responses of the experimental eyes were of normal pattern and amplitude, and were similar to those recorded by stimulation of the control eyes. Histologic studies of both experimental and control eyes did not show signs of structural damage. However, GFAP expression was increased in retinal Müller cells of the experimental eyes and not of the control eyes. Retinal penetration of ziv-aflibercept, as indicated by positive antihuman immunoreactivity, was observed 1 day postinjection and was strengthened during the next 7 days. At 14 days postinjection, ziv-aflibercept was not detected.ConclusionsZiv-aflibercept was found to be nontoxic to the retina of rabbits based on electrophysiologic testing and histologic examination. However, GFAP immunocytochemistry suggests mild retinal stress caused by the drug.Translational RelevanceIf proven safe, ziv-aflibercept may be a new affordable treatment option in conditions involving neovascularization and macular edema.

Safety and tolerability evaluation after repeated intravitreal injections of a humanized anti-VEGF-A monoclonal antibody (PRO-169) versus ranibizumab in New Zealand white rabbits

“…The limitations of this study were the model used, the scarce number of subjects in each group per product and number of intravitreal injections administered. The albino condition of the species used does modify the retinal response in the ERG due to scatter and reflection at the retinal layer [19,20]. However, the fact that this was a comparative evaluation between PRO-169 and ranibizumab in the same animal model parallels the results and attests to the value of the correlation of the studied parameters.…”

“…The amplitude ratio (experimental/control) served as an index of PRO-169 and ranibizumab effect on photopic retinal function. To assess retinal response, the data obtained at each ERG recording session was derived to the entire response-stimulus energy relationship and the V Max ratio (experimental/control eye) and the semi saturation constant difference (experimental–control) of the dark-adapted b-waves were calculated [ 19 ]. Previous studies have reported that with this approach, technical factors such as depth of anesthesia and duration of adaptation did not affect the evaluation of retinal function [ 12 , 13 , 20 ].…”

Electrophysiological evaluation and 18-month follow-up of two regimens with aflibercept for neovascular age-related macular degeneration

“…At the end of exposure and wash-out time, however, no reduction compared to baseline measurements could be detected. Short-term animal studies have not found retinal toxicity with ERG in the retina of rabbits with aflibercept at 4-week or ziv-aflibercept at 2-week follow-up [36,37]. Six-month and 1-year follow-up of 15 eyes of nAMD patients treated with ziv-aflibercept have not shown signs of toxicity on ffERG [29,30].…”

Ziv‐aflibercept: A cost‐effective, off‐label, highly potent antagonist of vascular endothelial growth factor

“…Twenty‐two albino rabbits (weighing 1.5–3 kg) each received a single 0.1 ml ziv‐aflibercept injection and a control group received normal saline (Ramon et al. ). Dark‐adapted electroretinograms showed no signs of damage in both groups at one and 4 weeks, and visual evoked responses were of normal pattern and amplitude at 4 weeks.…”