Ocular pharmacokinetics of intravitreally administered brimonidine and dexamethasone in animal models with and without blood-retinal barrier breakdown.

We compared ocular and systemic pharmacokinetics of brimonidine and dexamethasone following a single intravitreal dose in animals with blood-retinal barrier (BRB) breakdown and in healthy controls. We induced BRB breakdown in rabbits by intravitreal injection of recombinant human VEGF165 and choroidal neovascularization (CNV) in monkeys with laser. Control and disease animals then received single intravitreal injections of brimonidine alone, dexamethasone alone, or brimonidine in combination with dexamethasone. Ocular tissues and plasma were collected and quantified for drug concentration using LC-MS/MS assays. Statistical analysis was performed to compare the pharmacokinetic parameters between the control and disease animal models. In rabbits, brimonidine and dexamethasone exposure, as assessed by area under the drug concentration-time curve (AUC) in aqueous humor, retina, and choroid, was lower in disease than control animals, with a greater difference observed for dexamethasone than brimonidine. In monkeys, dexamethasone exposure was lower in disease than control animals for the central retina/choroid and peripheral choroid, whereas brimonidine exposure was lower in disease animals only in the central retina/choroid. Plasma exposure to both drugs was comparable between control and disease animals in both species. In animal models with a breakdown of the blood-retina barrier, drug clearance could be increased, resulting in lower drug concentration in ocular tissues compared to normal animals. However, the extent of difference may be compound- and disease model-specific. Therefore, extrapolation of ocular pharmacokinetic data obtained in normal animals to disease models for the purpose of pharmacokinetic/pharmacodynamic data analysis should be performed with caution.