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.

Fig 1. CONSORT flow diagram.

Fig 2. Brimonidine concentrations in the vitreous and the aqueous humors.

The solid horizontal line in each column indicates the mean of the included data points, and the dotted line parallel to the x-axis denotes the 2 nM brimonidine concentration that was shown to be neuroprotective in animals. The filled and open circles indicate vitreous humor and aqueous humor concentrations, respectively.

Fig 3. Correlations between drug concentrations in the aqueous and vitreous humors.

There was no significant correlation of the brimonidine (a) and the timolol (b) concentrations between in the aqueous humor and the vitreous.

Fig 4. Timolol concentrations in the vitreous and the aqueous humors.

The solid horizontal line in each column indicates the mean of included data points. The filled and open circles indicate concentrations in the vitreous humor and aqueous humor, respectively.

Fig 5. Linear correlations between brimonidine and timolol concentrations in the vitreous and aqueous humors.

The filled and open circles indicate concentrations in the vitreous humor and aqueous humor, respectively.