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D.C. Gale, L. Goulet, M. Batugo, D. Rewolinski, S. Anderson, C. Grove, T. Koudriakova; Ocular Pharmacokinetics in Single Compound and Cassette Dose Studies Following Sub–Tenon Administration in Dutch–Belted Rabbits . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5381.
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Purpose: Ocular neovascular diseases are the leading causes of vision loss and blindness in the developed world. One potential treatment for these diseases is to deliver a small molecule VEGFR tyrosine kinase inhibitor to the back of the eye via a sub–Tenon (ST) injection. AG–013958 is a small molecule VEGFR tyrosine kinase inhibitor currently in Phase I/II clinical trails. Rabbit PK was utilized to determine if ST administration provides adequate exposure of AG–013958 in the choroid. Sub–Tenon administration of several compounds in the same formulation (a cassette dose) to rabbits, was also examined as an approach to increase the number of compounds that can be tested in–vivo simultaneously. Methods: VEGF inhibitors, including AG–013958, were administered to dutch–belted rabbits via a ST injection as an individual compound or as a cassette. Blood and ocular tissues, including choroid (near the dose site and away from the dose site), retina, dose site tissue, vitreous, lens and aqueous humor were collected at various intervals from 1 day to 112 days post dose. Compound concentrations in the plasma and ocular tissues were determined by LC/MS/MS. Results: The highest concentration for the VEGFR inhibitors following ST dosing, was observed in the choroid. For AG–013958 administered as a single compound, choroid concentrations near the dose site ranged from 4895 ng/g to 10430 ng/g tissue over the duration of the study (112 days). AG–013958 levels appear to reach a steady state rapidly in the choroid, as early time points (7 days) have levels similar to those observed at later time points (112 days). Significantly lower concentrations were observed in the retina, plasma, vitreous humor and lens of the dosed eye for this compound. Tissue levels of VEGFR inhibitors dosed either as a single compound or in a cassette, when normalized to dose were similar. Conclusions: Following AG–013958 ST dosing in the rabbit, adequate exposure of the compound was confirmed in the target tissue (choroid). Results from the cassette dose rabbit ST experiments indicate that multiple compounds can be studied simultaneously using this experimental design. Cassette ST dosing of small molecule VEGFR inhibitors enables more rapid screening of compounds through comparison of compound levels in the same tissue/eye and requires less animals.
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