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Gabriela Burian, Jacques Gaudreault, Brian C Gilger, David Culp, Thi-Sau Migone; ICON-1 Pharmacokinetics after intravitreal and intravenous administration to rabbits. Invest. Ophthalmol. Vis. Sci. 2018;59(9):231. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
ICON-1, an immunoconjugate-1 fusion protein targeting Tissue Factor, was well tolerated and biologically active in a Phase II study in patients with wet age related macular degeneration. The objective of this study was to characterize its pharmacokinetics (PK) and safety after intravitreal (IVT) and intravenous (IV) administration in rabbits.
New Zealand White rabbits were assigned to one of the following group: G1: single dose ICON-1 IVT 600 μg/eye (N=24), G2: single dose ICON-1 IVT 300 μg/eye (N=24), G3: ICON-1 IVT 600 μg/eye on Day 1 and Day 8 (N=28) and G4: ICON-1 IV 3 mg/kg (N=6). For G1-G3, 4 animals/timepoints were sacrificed for collection of ocular matrices (retina, aqueous, vitreous). Plasma samples were collected over 7 days in all Groups. ICON-1 concentrations were quantified with a qualified ELISA (range 20-640 ng/mL). Vitreous and plasma samples were also assayed for the presence of anti-drug antibodies (ADA) with a qualified ECL bridging assay. Ocular examinations were conducted by a veterinary ophthalmologist. PK data were analyzed by non-compartmental and model dependent method, as appropriate.
Results of the vitreous PK are shown in Table below. ICON-1 administration showed no dose related ocular toxicities after the first/single administration, and moderate inflammation upon the 2nd administration (G3). Administration of single dose of 600 μg/eye resulted in vitreous concentrations about twice as high as those observed after a single dose of 300 μg/eye. When 600 μg/eye were administered 7 days apart, vitreous concentrations after the 2nd dose were 40% higher than following administration of a single 600 μg dose. ICON-1 retina concentrations declined in parallel to those in the vitreous and the concentrations were in the same range as those measured in the vitreous. After IVT administration, plasma concentrations declined in parallel with those in the vitreous. After IV administration, ICON-1 disappeared rapidly from the plasma with an initial half-life and beta half-life of 0.2 and 1.2 day, respectively. Data from other ocular matrices and plasma will be presented, as well as the projected human ocular exposure following IVT administration of various doses and regimens.
ICON-1 administration of 300 or 600 μg/eye was well tolerated in rabbits and was characterized by a good retina penetration and slow ocular elimination.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
ICON-1 Vitreous PK after IVT
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