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H.S. Younis, D. Matsumoto, K. Rittenhouse, W. Evering; Safety Assessment of a VEGF Receptor Tyrosine Kinase Inhibitor, AG–013958, in Rabbits and Primates Following Ocular Administration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3030.
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Purpose: AG–013958 is a vascular endothelial growth factor receptor tyrosine kinase inhibitor currently in Phase I/II clinical trails for the treatment of neovascular ocular diseases such as age–related macular degeneration. The safety of AG–013958 was assessed in a series of nonclinical studies in rabbits and primates. Methods: AG–013958 was administered by sub–Tenon (ST), intravitreal (IVT) or intravenous (IV) administration at doses 1–30–fold (in each eye) above the anticipated clinical dose. Results: A single ST dose (intended clinical route of administration) of AG–013958 produced no macroscopic compound–related findings for up to 13 weeks of treatment in primates. Microscopic evaluation of ocular and systemic tissues revealed the presence of macrophages at the ST dose site at 8 and 13 weeks post–treatment. This finding was consistent with a foreign body reaction to the presence of AG–013598 and was not associated with tissue injury or a fulminating inflammatory response. The primary finding in studies utilizing the IVT route of administration in rabbits and primates was the identification of test article grossly visible within the vitreous of both species for up to 8–weeks post injection. The presence of macrophages in the vitreous of rabbits with IVT dosing was considered a foreign body reaction. The doses selected for the IVT studies produced AG–013958 choroidal concentrations 2–3–fold above those tested with ST dosing. AG–013958 given as a single bolus IV dose at the highest IVT dose selected did not produce evidence of systemic toxicity up to five days after treatment. Conclusions: Overall, the preclinical safety assessment of AG–013958 demonstrates that the compound is well tolerated in rabbits and primates and supports the further development of this compound for the potential treatment of age related macular degeneration.
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