Ocular and Systemic Pharmacokinetics of AG–013958 With Sub–Tenon Administration To Cynomologus Monkeys

Abstract

Abstract: : Purpose: AG–013958, a VEGFR tyrosine kinase inhibitor, is in clinical development with ST administration for treatment of choroidal neovascularization associated with age–related macular degeneration (AMD). The ocular and systemic distribution of AG–013958 was evaluated in cynomolgus monkeys following sub–Tenon (ST) administration. Methods: Single–dose pharmacokinetic and toxicokinetic studies were conducted in male and female cynomolgus monkeys. AG–013958 was administered by ST injection in a sterile sucrose suspension at doses several–fold above possible clinical doses. Drug deposition was targeted posterior to the macula and adjacent to the optic nerve. Plasma was collected up to 48 hours post–dose. Ocular tissues, including choroid, retina, dose site tissue, ocular muscle, sclera, vitreous, iris–ciliary body, lens and aqueous humor were collected at various timepoints up to 16 weeks in one study. Dose site tissue, choroid, retina and vitreous concentrations of AG–013958 were measured at 13 weeks in a subsequent study. Plasma and tissue concentrations were evaluated by LC–MS/MS. Results: Plasma levels of AG–013958 were below 0.2 ng/mL in all but one sample for all dose groups. AG–013958 was observed up to 16 weeks in dose site tissue (conjunctiva and fatty tissue taken adjacent to the sclera at the site of administration) after a single ST dose at all dose levels tested. AG–013958 concentrations in choroid, the target tissue for AMD, were achieved within 3 days and were sustained for up to 16 weeks at 25 to 125 times the IC₉₀ of AG–013958 for VEGF–R2 inhibition in a rat retina PK/PD model. Retina concentrations of AG–013958 were generally at or below the IC₉₀. Ocular muscle, also encased by Tenon’s membrane, showed modest but variable levels. Concentrations in sclera samples increased up to 8 weeks, then decreased at 12 and 16 weeks. Very low levels of AG–013958 were observed in the iris–ciliary body or lens and low or no levels were detected in vitreous or aqueous humor. Conclusions: ST administration of AG–013958 suspension produced a depot of drug on the posterior surface of the sclera that provided sustained exposure to the choroid with little impact on peripheral tissues and no measurable systemic exposure. This data supports the preclinical safety assessment of AG–013958, reported separately, and also the ongoing clinical assessment of this compound for treatment of AMD.

Keywords: age-related macular degeneration • choroid: neovascularization • choroid