Intraocular Pharmacokinetics of Intravitreal Aflibercept (Eylea) in a Rabbit Model

Abstract

Citation: Park SJ, Choi Y, Na YM, et al. Intraocular pharmacokinetics of intravitreal aflibercept (eylea) in a rabbit model. Invest Ophthalmol Vis Sci. 2016;57:261257: -261757: . DOI:10.1167 PURPOSE. We determined the intraocular pharmacokinetic properties of intravitreally injected aflibercept (Eylea) in a rabbit model. METHODS.Aflibercept was injected intravitreally in 21 eyes from New Zealand White rabbits. The eyes were enucleated 1, 24, 48, 120, 216, 360, and 720 hours (1, 2, 5, 9, 15, and 30 days, respectively) after injection and immediately frozen at À808C. The concentrations of aflibercept in the vitreous, aqueous humor, and retina/choroid were determined by performing an indirect enzyme-linked immunosorbent assay, and analyzed to understand the pharmacokinetic properties of the drug. RESULTS.The maximum concentration of aflibercept was observed 1, 48 (2 days), and 24 (1 day) hours after intravitreal administration in the vitreous, aqueous humor, and retina/ choroid, respectively. The one-compartment model was selected as the final model for all three ocular tissues. In the vitreous, aqueous humor, and retina/choroid, the estimated halflives of aflibercept were 94.1, 48.0, and 58.2 hours, and the estimated mean residence times (MRTs) were 135.8, 69.2, and 84.0 hours, respectively. The area under curve from time 0 to the end point (AUC last ) was 135,810.6 hours 3 lg/mL for the vitreous, 13,889.7 hours 3 lg/ mL for the aqueous humor, and 2453.1 hours 3 lg/g for the retina/choroid. CONCLUSIONS.In rabbits, the vitreous half-life of aflibercept is 94.1 hours (3.92 days). This is shorter than that of bevacizumab (6.99 days), and longer than that of ranibizumab (2.51 days) and VEGF-Trap (3.63 days).

Role of the Fc Region in the Vitreous Half-Life of Anti-VEGF Drugs

“…The intraocular PK of VEGF-Trap and FcfVEGF-Trap were evaluated using same experimental design as in our previous studies. [6][7][8][9] Intramuscular injection of 15 mg/kg Zoletil (a mixture of tiletamine and zolazepam; Virbac Laboratories, Carros, France) and 5 mg/kg xylazine, and a topical ophthalmic anesthetic (1% proparacaine hydrochloride, Alcaine; Alcon Laboratories, Inc., Fort Worth, TX, USA) were used for anesthesia. Eyes under investigation were dilated with eye drops containing a mixture of phenylephrine and tropicamide.…”

“…5 In fact, it was previously reported that the vitreous half-life of ranibizumab (2.75 days) was shorter than those of bevacizumab (7.06 days) and aflibercept (3.63 days) in rabbits. [6][7][8][9] Intravitreally administered anti-VEGF drugs reach first and in a larger proportion in the external layer (pericytes) and then reach the inner layer (endothelial cells) after crossing the blood-retina barrier. 10 Recent studies reported that the elimination of intravitreally administered IgG across the blood-retina barrier into the systemic circulation is mediated by the neonatal Fc receptor (FcRn), which is expressed in the retinal pigment epithelium and endothelial cells of the retinal and choroidal vasculature.…”

“…[6][7][8][9] Based on our experience and skills in ocular PK, we comparatively studied the ocular PK of VEGF-Trap and a newly synthesized Fc region-free VEGF-Trap (FcfVEGF-Trap) to uncover the role of Fc region in ocular PK.…”

Generation and characterization of ABBV642, a dual variable domain immunoglobulin molecule (DVD-Ig) that potently neutralizes VEGF and PDGF-BB and is designed for the treatment of exudative age-related macular degeneration

“…Increase in molecular size was reported to have a weak correlation with increase in residence time in the vitreous cavity. 21,22,23 A full-length 200 kDa DVD-Ig format with a larger molecular size was therefore selected for ABBV642. The third factor considered was safety.…”

“…Although prolonged residence time in the eye is desirable, prolonged residence in systemic circulation is not because systemic suppression of VEGF is associated with hemorrhagic and thromboembolic complications. 24 The Fc neonatal receptor (FcRn) is responsible for prolonged serum residence, 25 but is not required for ocular 21,23 half-life of immunoglobulin molecules, and therefore FcRn binding was disabled in ABBV642 by introduction of a H435A (FcRn null) mutation. 26 Endothelial cells release paracrine PDGF-BB, which is retained proximally by heparin sulfate proteoglycan.…”