Comprehensive Ocular and Systemic Pharmacokinetics of Brinzolamide in Rabbits After Intracameral, Topical, and Intravenous Administration

Brinzolamide is a topical Carbonic Anhydrase Inhibitor which reduces the production of aqueous humor in the ciliary body, thereby reducing intra-ocular pressure. It is formulated as an ophthalmic suspension. The pharmacokinetics of ocular suspensions is not well understood. The objective of this study was to characterize the pharmacokinetics of brinzolamide in rabbit aqueous humor, iris-ciliary body, plasma, and whole blood. New Zealand White rabbits were dosed via intracameral, topical and intravenous administration. After intracameral administration (4.5 μg) of solubilized brinzolamide, aqueous humor concentrations were described with a two-compartment model, the estimated clearance was 4.12 μL/min, apparent volume of distribution at steady-state 673 μL, and terminal half-life 3.4 h. After topical administration of 1% brinzolamide suspension (500 μg), absolute bioavailability based on aqueous humor AUC_0-∞ was 0.10%. After intravenous administration of brinzolamide solution (0.75 mg/kg) elimination half-life in plasma and whole blood appeared to be over two weeks. The ratios of the measured concentrations of irisciliary body to whole blood, to plasma, and to aqueous humor concentrations enabled direct comparisons, and helped identify the significant contribution of the conjunctival-scleral pathways of absorption to the ciliary body. This study shows for the first-time the absolute bioavailability in aqueous humor and provides comprehensive pharmacokinetic parameters following administration of a topical suspension.