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Jie Shen, Chandrasekar Durairaj, Ton Lin, Yan Liu, James Burke; Comparison of Ocular Pharmacokinetics of Brimonidine and Dexamethasone in Normal Animal vs. Animal Models with Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1243.
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© ARVO (1962-2015); The Authors (2016-present)
To compare ocular pharmacokinetic profile of brimonidine and dexamethasone in multiple ocular tissues following intravitreal bolus doses of either brimonidine or dexamethasone in normal animals (rabbits and monkeys) versus animal models with choroidal neovascularisation (CNV).
CNV was induced in Dutch Belt rabbits by injecting 1 μg of recombinant human VEGF165 into the vitreous, and in monkeys with laser. The rabbits were dosed in the pharmacokinetic study two days post VEGF injection and the monkeys were dosed 2 weeks post laser treatment. Both normal and CNV animals received single bolus intravitreal injections of brimonidine (50 μg) and dexamethasone (400 μg). Rabbits were euthanized at 0.5, 1, 2, 4, 8, 10, 12, and 24 hr post-dose and monkeys were euthanized at 1, 4, 8, 13, 24, and 48 hr post-dose. Aqueous humor, vitreous humor, retina, choroid, and plasma were collected from each animal and quantified for brimonidine and dexamethasone using LC MS/MS assays. The pharmacokinetic data was compared via the bootstrapping technique. Statistical analysis was performed using SAS® (Version 9.2).
Mean pharmacokinetic parameters in selected matrices for comparison between normal and CNV animals are presented in the table shown.
In animal CNV models with a breakdown of the blood retina barrier, clearance of drugs administered intravitreally could be increased resulting in lower drug concentration in ocular tissues when compared to normal animals. However, the extent of change may be compound specific and animal model specific. Between the two compounds tested, dexamethasone clearance appeared to be altered more consistently and significantly in rabbits, with up to 45% lower drug exposure in the CNV model compared to the normal animals. Therefore, extrapolation of ocular PK obtained in normal animals to CNV animals for the purpose of PKPD data analysis should be performed with caution.
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