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J. Gaudreault, M. Reich, A. Arata, J. Rusit, N. Pelletier, V. Shiu; Ocular Pharmacokinetics and Antipermeability Effect of rhuFab V2 in Animals . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3942.
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Purpose: rhuFab V2, an antibody fragment that binds vascular endothelial growth factor (VEGF) with high affinity, is in clinical trials for the treatment of neovascular age related macular degeneration. A series of studies were undertaken to 1) characterize the vitreous pharmacokinetics of rhuFab V2 in NZW rabbits and 2) characterize the effect of rhuFab V2 inhibition on VEGF-induced permeability in guinea pigs (Miles assay). Methods: 1) Vitreous PK: A total of 52 rabbits received a single intravitreal (ITV) 500 µg/eye of rhuFab V2, and rabbits were euthanized over 14 days for collection of vitreous humor. rhuFab V2 concentrations and antibodies against rhuFab V2 were determined by ELISA, and data analyzed by compartmental methods. 2) Permeability assay: Following intracardiac injection of Evans Blue, hairless guinea pigs received intradermal (ID) dorsum injections of rhuFab V2 (0-6000 ng/mL) concomitantly with rhVEGF165 (100 ng/mL). One hour following ID injection, the animals were euthanized, pelts harvested and photographed for quantification of dye leakage into the injection sites. The relationship between rhuFab V2 concentration and dye leakage was characterized using an Emax model. Results: 1) rhuFab V2 pharmacokinetics was characterized by a clearance of ~0.3 mL/day, a distribution volume of 1.3 mL and a terminal t1/2 of 3 days. 2) rhuFab V2 inhibition of VEGF-induced permeability occurred in a concentration-dependent manner. Conclusions: rhuFab V2 ocular pharmacokinetics was well characterized, and inhibition of VEGF-induced permeability was demonstrated in a Miles Assay. These results are consistent with clinical data showing rapid decrease in retinal thickness in AMD subjects following ITV administration of rhuFab V2.
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