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L. Cheng, M. Brar, R. Yuson, F. Mojana, P. S. Gill, W. R. Freeman; Intraocular Properties and Intraocular Pharmacokinetics of a Novel Therapeutic Antagonist of Ephb4/ephrinb2 Signaling to Inhibit Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5159.
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The receptor tyrosine kinase EphB4 and its ligand EphrinB2 are expressed on venous and arterial endothelial cells respectively, and play a crucial role in vascular development and maturation of newly forming vessels at the sites of remodeling. A soluble form of EphB4 inhibits choroidal angiogenesis in in vitro choroid endotheleial cell migration and tube formation assays and in vivo in laser induced choroidal neovascularization models. Interference with EphB4-EphrinB2 interaction thus provides a distinct and novel approach for inhibition of angiogenesis. Current study is to investigate the safety and ocular pharmacokinetics of sEphB4, an antagonist of EphB4/EphrinB2 signaling, after a single intravitreal injection.
Five doses (80, 180, 465, and 1000 µg per eye) and three rabbit eyes were used for each testing dose. The fellow eyes were used as internal control and injected with equivalent volume of 50 µl of PBS. The eyes were monitored by biomicroscopy, indirect ophthalmoscopy, tonometry, and electroretinogram (ERG). Histology was performed after sacrifice. 80 µg/eye was used for pharmacokinetic study and seven post-intravitreal injection time points (1, 3, 7, 14, 28, 35, 56 days) with three rabbits eyes on each time point were used. Different intraocular tissues from the same eyes were isolated and sEphB4 was quantified by ELISA analysis.
The minimum effective dose of sEphB4 to inhibit angiogenesis is 2 nanomolar (116ng/ml). No ocular toxicity was noted even with the highest dose of 1000 µg/eye. Pharmacokinetic study demonstrated a very similar pharmacokinetics in both vitreous and retina, with the half-life of 4.6 days in vitreous and 6.3 days in retina. Vitreous Cmax was 29.6 µg/ml and retina Cmax was 30.5 µg/ml at Tmax of day 3. sEph B4 in choroids had a lower Cmax of 16 µg/ml at Tmax of day 7 as well as the half-life of 5.5 days.
The study showed intravitreal use of sEphB4 is safe and its intraocular pharmacokinetics is superior to Lucentis and Avastin. Our Pharmacokinetic studies indicate therapeutic levels in the retina and choroid are present after a single intravitreal 1000 microgram dose for over 50 days suggesting once every two months dosing intravitreally may be effective in the treatment of choroidal neovascularization in age related macular degeneration.
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