Abstract
Purpose :
Brinzolamide is a topical carbonic anhydrase inhibitor which reduces the production of aqueous humor (AH) in the ciliary body, thereby reducing intra-ocular pressure (IOP). It is formulated as an ophthalmic suspension to enhance residence time on the ocular surface and thereby increase drug availability. Brinzolamide accumulates in red blood cells, which express the carbonic anhydrase enzyme, resulting in its long half-life. The objective of this study was to characterize the pharmacokinetics of brinzolamide in relevant ocular and systemic compartments of rabbits: aqueous humor (AH), iris/ciliary body (ICB), plasma, and whole blood (WB).
Methods :
New Zealand White rabbits were dosed via intracameral (IC), topical and intravenous (IV) administration.
Results :
After IC administration (4.5 µg/eye) of fully solubilized brinzolamide, the AH concentration curve was described with a two-compartment model, and estimated intracameral clearance was 4.2 µL/min, apparent volume of distribution at steady-state 690 µL, and terminal half-life 3.4 h, respectively. AUC0-24 h in ICB was determined to be 40% of AH. However, ICB concentration was observed to decline very slowly after 8 h, and ICB/AH concentration ratio at 24 h (the last sampling time) was 7.5. After topical administration of 1% brinzolamide suspension (50 µL/eye and 500 µg/eye), absolute bioavailability based on AH AUCinf values was 0.11% (compared to 100% with IC injection). After IV administration of brinzolamide solution (0.75 mg/kg) with 2-week sampling period, elimination half-life in plasma and WB appeared to be over 2 weeks. After 8 h, WB/plasma concentration ratio remained approximately constant at 400-950. The measured concentration for ICB at the terminal sampling time point, were used to calculate mean ICB/WB, ICB/plasma, and ICB/AH concentration ratios.
Conclusions :
In summary brinzolamide clearance from AH was only slightly higher than the normal AH turnover in rabbits (3 µL/min). A comparison of the ICB/AH AUC ratios after topical versus IC administration, suggests a major contribution of a non-corneal absorption route towards ICB concentrations. Additional experiments will be performed to confirm the processes contributing to the higher exposure in the ICB. Understanding the clearance and other PK parameters will help support model-informed ocular drug development.
This is a 2020 ARVO Annual Meeting abstract.