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C.B. Hoyng, J.R. Vingerling, J.M. M. Hooymans, K.J. Klamerus, H. Younis, D. Khalil, B. Scassellati–Sforzolini, S. Russell, R.O. Schlingemann; AG–013958 (VEGFR Inhibitor) Achieves Effective Choroidal Concentrations With Minimal Systemic Effects in Cynomolgus Monkeys and Humans With Age–Related Macular Disease . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2365.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To compare clinical exposure of AG–013958 (VEGFR inhibitor) to preclinical tissue exposure. Methods: The initial clinical results in 21 patients with subfoveal choroidal neovascularization associated with AMD and the preclinical tissue data in monkeys is reported. Clinically, AG–013958 was given by sub Tenon administration. Plasma samples for AG–013958 concentrations were collected at day 1 (0,10,30 and 60 minutes), days 2–4, weeks 4, 8 and 13 post–AG–013958 administration. Patients were questioned at each visit for adverse events (AEs). Preclinically, 13 (6M/7F) cynomolgus monkeys administered AG–013958 once had plasma, choroid and dose site tissues examined 13 weeks postdose. Results: 16 (76%) patients reported AEs; 4 reported as related to administration procedure (eye pain, increased lacrimation, reaction [sand–like feeling], conjunctival hyperaemia) 3 to drug (dizziness, feeling abnormal, eye pain) and 9 to other. All AEs reported as related to drug or administration procedure were Grade 1. In 16 patients, 9% of plasma samples had measurable AG–013958 plasma concentrations; mean ± SD [range] of 13.5 ± 3.5 [10–22] pg/mL with an LC–MS–MS assay sensitivity of 10 pg/mL. Similarly, minimal systemic exposure was observed in cynomolgus monkeys; there were no measurable plasma AG–013958 concentrations (assay sensitivity 0.2 ng/mL) during the 13 weeks postdose. Dose site tissue contained about 2% of the dose at 13 weeks while the choroid contained about 25–fold greater than the target IC90. Conclusions: Clinically, AG–013958 has resulted in minimal systemic exposure as demonstrated by Grade 1 AEs in 44% of patients (reported as related to drug or administration) and plasma concentrations occasionally above the 10 pg/mL sensitivity limit of the assay. This is similar to preclinical studies in cynomolgus monkeys where systemic exposures were below the limit of quantification and at the same time choroid concentrations were at least 25–fold greater than the target IC90.
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