Ocular and systemic pharmacokinetics of brimonidine and brinzolamide after topical administration in rabbits: comparison between fixed-combination and single-drug formulations

ABSTRACT

Aim

The aim of this study was to compare the ocular and systemic absorption of brimonidine (BMD) and brinzolamide (BZM) in rabbits after the topical administration of a fixed-combination ophthalmic suspension of 0.1% BMD tartrate and 1% BZM (FCBB) with that after the administration of the respective single-drug formulations.

Materials and Methods

Ocular and systemic drug absorption was estimated by determining BMD and BZM concentrations in the aqueous humor, retina/choroid, vitreous body, and blood/plasma by liquid chromatography/tandem mass spectrometry after the administration of FCBB, 0.1% BMD tartrate ophthalmic solution (0.1% BMD), or 1% BZM ophthalmic suspension (1% BZM) to rabbits.

Results

In concomitant administration, instilling 0.1% BMD and 1% BZM successively without interval lowered aqueous humor concentrations of both drugs compared to those observed with a 5-min interval. After FCBB administration, BMD and BZM concentrations in the aqueous humor were comparable with those observed after the administration of 0.1% BMD and 1% BZM, whereas BMD concentrations in posterior ocular tissues were equal to or higher than those observed after 0.1% BMD. Plasma BMD concentrations following the administration of FCBB were 0.8-fold lower than those after 0.1% BMD; no remarkable differences were observed in blood BZM concentrations for both formulations.

Conclusions

FCBB achieved drug distribution in the aqueous humor and systemic exposure that were comparable to those for the single-drug formulations. The viscosity of FCBB may increase BMD distribution in the retina/choroid. The administration interval affects ocular drug absorption with the concomitant administration of 0.1% BMD and 1% BZM, which can be overcome by using the fixed-combination of both drugs.

KEYWORDS:

• Administration interval
• brimonidine
• brinzolamide
• fixed-combination
• pharmacokinetics

Authors’ contributions

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article and take responsibility for the integrity of the work as a whole. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Acknowledgments

The authors thank their co-workers in the DMPK team of Senju Pharmaceutical Co. Ltd. for their technical assistance in the distribution study and Mr. Takuro Sekiya and Dr. Yu Haranosono for their helpful advice in the preparation of this paper.

Declaration of interest

All authors of this paper, Gen Suzuki, Eriko Kunikane, Wakasa Shigemi, Keisuke Shinno, Seiko Kozai, Masaaki Kurata, and Akio Kawamura, declare that they have no conflicts of interest. All authors of this paper are employees of Senju Pharmaceutical Co., Ltd.

Ethics approval

All institutional and national guidelines for the care and use of laboratory animals were followed.

Consent for publication

All named authors have given their approval for this version to be published.

Additional information

Funding

This research and publication processing costs were supported by Senju Pharmaceutical Co., Ltd.