Abstract
Purpose :
BrimocholTM (Visus Therapeutics) is a fixed combination of the cholinergic miotic agent carbachol and the alpha-2 agonist brimonidine that is being developed as a topical ocular product for the treatment of presbyopia. The purpose of these two nonclinical studies was to evaluate ocular distribution and effect on pupil diameter following administration of Brimochol in pigmented rabbits.
Methods :
Dutch Belted rabbits (4/group) received a single unilateral administration of 35 µl of Brimochol or carbachol 2.75%, while the contralateral eye received phosphate-buffered saline (PBS). Pupil diameter was measured in conscious animals using a digital pupillometer under scotopic (0 lux), low mesopic (0.3 lux), high mesopic (3 lux), and photopic (669 lux) conditions at baseline and at various time points out to 12 hours postdose. Ophthalmic exams were conducted at 0.25 and 2 hours postdose using the Hackett McDonald scoring system. In a separate study, rabbits received a bilateral administration of Brimochol or carbachol, and concentrations of brimonidine and carbachol were measured in ocular matrices (4 eyes/time point) using liquid chromatography and tandem mass spectrometry.
Results :
Brimochol decreased pupil size in all lighting conditions to a greater extent than carbachol alone, and the miotic effect was sustained for up to 12 hours. An improved ocular tolerability profile was observed for Brimochol compared to carbachol alone. The mean maximum concentration (Cmax) for carbachol in the iris ciliary body (ICB) was 32.8 ng/g and the mean area under the curve (AUC) was 223h*ng/g for Brimochol, compared to 17.7 ng/g and 157 h*ng/g, respectively, for carbachol alone, indicating increased exposure to carbachol following Brimochol administration. Time at Cmax (Tmax) was similar between groups.
Conclusions :
Brimochol demonstrated effectiveness at reducing pupil size in rabbits for 12 hours and had a greater effect on pupil size than carbachol 2.75% alone. The addition of brimonidine appears to improve the ocular tolerance profile compared to carbachol alone. Perhaps by altering aqueous dynamics, the addition of brimonidine also tends to increase the extent and duration of carbachol exposure in the target tissue.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.