Brimonidine and timolol concentrations in the human vitreous and aqueous humors after topical instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution: An interventional study

Abstract

Purpose To evaluate the concentrations of brimonidine and timolol in the vitreous and aqueous humors after instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution. Methods This single-arm open-label interventional study included patients with macular holes or idiopathic epiretinal membranes who were scheduled for vitrectomy. Written informed consent was obtained from all participants. A 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution was administered topically twice daily for 1 week preoperatively. The vitreous and aqueous humors were sampled before vitrectomy, and brimonidine and timolol concentrations were quantified using liquid chromatography-tandem spectrometry. This study was registered with the Japan Registry of Clinical Trials (jRCT, ID jRCTs051200008; date of access and registration: April 28, 2020). The study protocol was approved by the University of Fukui Certified Review Board (CRB) and complied with the tenets of the Declaration of Helsinki. Results Eight eyes of eight patients (7 phakic eyes and 1 pseudophakic eye) were included in this study. The mean brimonidine concentrations in the vitreous and aqueous humors were 5.04 ± 4.08 nM and 324 ± 172 nM, respectively. Five of the eight patients had brimonidine concentrations >2 nM in the vitreous humor, which is necessary to activate α2 receptors. The mean timolol concentrations in the vitreous and aqueous humors were 65.6 ± 56.0 nM and 3,160 ± 1,570 nM, respectively. Brimonidine concentrations showed significant positive correlations with timolol concentrations in the vitreous humor (P < 0.0001, R2 = 0.97) and aqueous humor (P < 0.0001, R2 = 0.96). Conclusions The majority of patients who received a 0.1% brimonidine tartrate and 0.5% timolol topical fixed-combination ophthalmic solution showed a brimonidine concentration >2 nM in the vitreous humor. Brimonidine and timolol may be distributed in the ocular tissues through an identical pathway after topical instillation.

Ocular Distribution of Brimonidine and Brinzolamide after Topical Instillation of a 0.1% Brimonidine Tartrate and 1% Brinzolamide Fixed-Combination Ophthalmic Suspension: An Interventional Study

“…Previous studies investigated the concentration of brimonidine in vitreous humor after the topical administration of 0.1% (Aifagan ® , Senju Pharmaceutical Co., Ltd.) [ 33 ], 0.15% (Alphagan ® ; Allergan, Dublin, Ireland) [ 34 ] and 0.2% (Alphagan ® ; Allergan) [ 35 ] brimonidine tartrate ophthalmic solutions, and 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution (Aibeta ® ; Senju Pharmaceutical Co., Ltd.) [ 37 ]. Ailamide ® (Senju Pharmaceutical Co., Ltd.) is an ophthalmic suspension containing brinzolamide.…”

“…In our previous investigation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution (Aibeta ® ; Senju Pharmaceutical Co., Ltd.), the sample size was 8 patients [ 37 ]. The University of Fukui Certified Review Board approved the study design to minimize the risk of adverse events to patients because the instillation of Ailamide ® (Senju Pharmaceutical Co., Ltd.) had no indication for the treatment of patients with macular holes or idiopathic epiretinal membranes planning to undergo vitrectomy.…”

“…The efficiency of drug delivery into ocular tissues is influenced by differences in the preservatives used, pH, and viscosity between the fixed-combination and single agents, as well as interactions between components. Our previous study using a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution revealed that 63% of vitreous samples contained a concentration of brimonidine > 2 nM [ 37 ]. The brimonidine tartrate ophthalmic solution was homogenous.…”

Patient Factors Influencing Intraocular Penetration of Brimonidine-Related Eye Drops in Adults: A Post Hoc Pooled Analysis

“…This post hoc pooled analysis integrated and reanalyzed data sourced from three clinical studies that determined brimonidine concentrations in the aqueous and vitreous humor after the topical application of the following eye drops containing brimonidine: 0.1% brimonidine tartrate ophthalmic solution (Aiphagan Ò ; Senju Pharmaceutical Co., Ltd., Osaka, Japan), 0.1% brimonidine tartrate and 0.5% timolol (equivalent to 0.68% timolol maleate) fixedcombination ophthalmic solution (Aibeta Ò ; Senju Pharmaceutical Co., Ltd.) and 0.1% brimonidine tartrate and 1% brinzolamide fixed-combination suspension (Ailamide Ò ; Senju Pharmaceutical Co., Ltd.) [8][9][10] (Tables 1 and 2).…”

“…No correlation was found among brimonidine, timolol or brinzolamide concentrations in the aqueous and vitreous humor and corneal thickness, corneal endothelial cell density, tear secretion (Schirmer's test), eye axial length, height or BMI (Figs. 5,6,7,8,9,10).…”