OSLI Retina

December 2019

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December 2019 · Vol. 50, No. 12 785 ■ E X P E R I M E N T A L S C I E N C E ■ Safety and Bioavailability of Complete and Half-Dose Intravitreal Ziv-Aflibercept in an Experimental Model: Contralateral Eye Study Alireza Lashay, MD; Elham Delrish, PhD; Elham Ashrafi, PhD; Morteza Movassat, MD; Fahimeh Asadi-Amoli, MD; Rassoul Dinarvand, PhD; Mojtaba Abrishami, MD BACKGROUND AND OBJECTIVE: To evaluate the safety and bioavailability of complete and half-dose of intra- vitreal 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 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 enucle- ated. 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. RESULTS: No serious drug-related ocular inflammation and toxicity or systemic adverse events were identi- fied. 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 in- jection, 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 com- plete 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. 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. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:785-790.] INTRODUCTION The major angiogenic driver for uncontrolled neo- vascularization has been introduced as vascular en- dothelial growth factor (VEGF). 1 VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF) are five members of VEGF family in mammalians. 2 Clinical research has demonstrated the significant role of VEGF-A in developing ocular neovascular- ization, such as diabetic retinopathy and age-related macular degeneration (AMD), with the application of VEGF-A inhibitors. 3 Aflibercept (Eylea; Regeneron, Tarrytown, NY), or VEGF Trap-eye, is the late mem- ber of the anti-VEGF family. 4 Since VEGFR-1 has a higher affinity for VEGF than VEGFR-2, drug devel- opers have employed its binding sequences for VEGF Trap-eye. 5 Aflibercept, which is a 115-kDA recombi- nant protein, was manufactured from portions of the human VEGFR bound to the FC portion of a human Immunoglobulin G1 and approved by the U.S. Food and Drug Administration (FDA) in November 2011. 6 Anti-VEGF therapy is the current remedy for AMD, diabetic macular edema (DME), and other uncontrolled ocular neovascularizations. 7 Need of monthly visits and intravitreal procedures with unde- sirable side effects have motivated researchers to find a way to decrease number of injections and monitor- From Eye Research Center, Farabi Eye Hospital, Tehran University of Medi- cal Sciences, Tehran, Iran (AL, ED, EA, MM, FAA); Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (RD); and Eye Research Center, Mashhad University of Medical Sci- ences, Mashhad, Iran (MA). Originally submitted September 5, 2018. Revision received March 31, 2019. Accepted for publication July 3, 2019. Presented at the 8th Annual Meeting of the Iranian Research Association for Vision and Ophthalmology as an oral presentation. The authors report no relevant financial disclosures. The authors would like to thank Sara Aghajanpour, MSc, director of the animal lab, as well as Leyla Javdane, BSc, and Maryam Nemati Soldarogh, BSc, of the Angiography Department of Farabi Eye Hospital, for their help in the process of this report. Address correspondence to Mojtaba Abrishami, MD, Khatam-al-Anbia Eye Hospital, Eye Research Center, Mashhad University of Medical Sciences, Qarani Blvd., Mashhad 9195965919, Iran; email: mojtaba_abrishami@ yahoo.com. doi: 10.3928/23258160-20191119-06

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