Safety and Bioavailability of Complete and Half-Dose Intravitreal Ziv-Aflibercept in an Experimental Model: Contralateral Eye Study.

BACKGROUND AND OBJECTIVE: To evaluate the safety and bioavailability of complete and half-dose of intravitreal ziv-aflibercept (IVZ) in an experimental model. MATERIALS AND METHODS: Thirty-two eyes of 16 male rabbits received one IVZ injection under anesthesia and the operating microscope. All right and left eyes received 1,250 mu g/0.05 mL and 625 mu g/0.05 mL of ziv-aflibercepl, respectively. Then, rabbits were randomly allocated to four groups (four rabbits in each group). The rabbits were euthanized at predesignated intervals (at 24, 168, 336, and 720 hours), and the eyes were enuclealed. Indirect ophthalinoscopy, vitreous sampling, and electrophysiological recordings were obtained before euthanization. Histological examination was performed after enucleation. Vitreous samples were evaluated by enzyme-linked immunosorbent assay to measure the concentration of aflibercept. RESULTS: No serious drug-related ocular inflammation and toxicity or systemic adverse events were identified. Electroretinogram findings showed no significant difference to the baseline measurements. Remaining vitreal concentrations of ziv-aflibercept injection for the 625 mu g/mL group were 416 mu g/mL, 349 mu g/mL, 124 mu g/mL, 41.2 mu g/mL, and 18.1 mu g/mL (+/- 10 mu g/mL) and for the 1,250 mu g/mL group were 833 mu g/mL, 737 mu g/ mL, 284 mu g/mL, 87.3 mu g/mL, and 38.2 mu g/mL (+/- 10 mu g/mL), at zero, 24, 168, 336, and 720 hours after injection, respectively. The vitreous concentration of aflibercept was analyzed by one-compartment model. The area under curve from time 0 to the end point (AUC last) was 147,637 hours x mu g/mL for the complete dose group (1,250 mu g/0.05mL) and 68,498 hours x mu g/mL for the half-dose group (625 mu g/0.05 mL). The assessed vitreous half-life of ziv-aflibercept was 113 hours in both groups. CONCLUSIONS: IVZ proved to be safe and well tolerated, even in the complete dose group. It seems to be a cost-effective therapeutic option for the treatment of retinal vascular diseases. However, the long-term safety and efficacy of intravitreal ziv-aflibercept remain unknown.