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

• Published in: Ophthalmic surgery, lasers & imaging retina Vol. 50; no. 12; p. 785
• Main Authors: Lashay, Alireza, Delrish, Elham, Ashrafi, Elham, Movassat, Morteza, Asadi-Amoli, Fahimeh, Dinarvand, Rassoul, Abrishami, Mojtaba
• Format: Journal Article
• Language: English
• Published: United States 01-12-2019
• Subjects: Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacokinetics; Animals; Biological Availability; Electroretinography; Enzyme-Linked Immunosorbent Assay; Half-Life; Intravitreal Injections; Male; Models, Animal; Ophthalmoscopy; Pilot Projects; Rabbits; Receptors, Vascular Endothelial Growth Factor - administration & dosage; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - pharmacokinetics; Retina - physiology; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vitreous Body - metabolism
• DOI: 10.3928/23258160-20191119-06
• EISSN: 2325-8179

To evaluate the safety and bioavailability of complete and half-dose of intravitreal ziv-aflibercept (IVZ) in an experimental model.
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 μg/0.05 mL and 625 μg/0.05 mL of ziv-aflibercept, 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 enucleated. Indirect ophthalmoscopy, 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.
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 μg/mL group were 416 μg/mL, 349 μg/mL, 124 μg/mL, 41.2 μg/mL, and 18.1 μg/mL (± 10 μg/mL) and for the 1,250 μg/mL group were 833 μg/mL, 737 μg/mL, 284 μg/mL, 87.3 μg/mL, and 38.2 μg/mL (± 10 μg/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 × μg/mL for the complete dose group (1,250 μg/0.05mL) and 68,498 hours × μg/mL for the half-dose group (625 μg/0.05 mL). The assessed vitreous half-life of ziv-aflibercept was 113 hours in both groups.
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. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:785-790.].