Impact of Variations in Critical Quality Attributes of Brinzolamide Ophthalmic Suspensions on Preclinical Pharmacokinetics and Pharmacodynamics Following Once-Daily Topical Instillations

Abstract

Purpose : Brinzolamide ophthalmic suspensions are indicated for treatment of elevated intraocular pressure (IOP), a major risk factor for optic nerve damage and glaucomatous visual field loss. Therefore, this study focuses on understanding the relationship between critical quality attributes (CQAs) of ophthalmic suspensions and their pharmacokinetic/pharmacodynamic (PK/PD) performance in furtherance of safe and effective generic products for treatment of IOP.

Methods : Multi-dose, parallel study with once-daily ophthalmic instillations of brinzolamide ophthalmic suspensions (0.5 mg/eye) for 14 days in NZW rabbits. Test formulations (BRZ_001 – 005) and reference product Azopt were characterized for particle size distribution (PSD) and apparent viscosity. IOP measurements via applanation tonometer, at the same time of day, for 5 days prior dosing and up to 14 days of daily dosing. Relevant ocular tissues were harvested for processing and drug quantification on Days 7 and 14.

Results : Differences in PD could not be correlated with differences in CQAs. At 1 h of Day 14, BRZ_002 and BRZ_005, with similar particle size but ranging in viscosity from average to the highest, respectively, showed the highest reduction of IOP. BRZ_001, with the smallest particle size but second to highest viscosity, showed similar IOP reduction as BRZ_003, with the largest particle size and average viscosity. In addition, differences in CQAs of all formulations did not lead to significant PK differences in aqueous humor (AH) and iris-ciliary body (ICB). Minor trends were noted in cornea and conjunctiva, likely due to a confounded effect of PSD reduction and viscosity increase on retention and absorption.

Conclusions : Ophthalmic suspensions varying in select CQAs did not lead to remarkable differences in PK/PD of brinzolamide under once daily dosing regimen. These observations could be attributed to the sparser dosing regimen assessed for brinzolamide ophthalmic suspension, likely hindering drug concentration build-up in ocular tissues and leading to confounded observations. This study highlights current challenges in assessing drug product performance equivalence for brinzolamide ophthalmic suspensions.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Day 14 of Once-Daily Dosing of Brinzolamide Ophthalmic Suspensions. (Left) Mean IOP change. (Right) Mean drug concentration versus time in ICB.