Examining pharmacological controls of presbyopia

Carbachol may have an even greater miotic effect on younger presbyopes than in the older glaucoma patients we once prescribed it for, because younger patients have more pronounced sympathetic iris tone and thus more vigorous pupillary dilation. Three novel formulations, including 2 fixed-dose combinations of carbachol and brimonidine tartrate (Brimochol and Brimochol F) and a similarly formulated preservative-free carbachol, were recently tested in the company's phase 2 VIVID clinical trial. [...]previous evidence suggests that combining brimonidine tartrate with carbachol could have additive contributions.4-6 Brimonidine, a sympatholytic a-2 agonist, prevents pupil dilation by inhibiting the contraction of the iris dilator muscle and may also inhibit contraction of the ciliary muscle. [...]its activity is synergistic to pupillary constriction and potentially alleviates the customary dull ache or brow pain experienced by many patients on miotics. Presumably, by altering aqueous dynamics, brimonidine has also been shown to increase the bioavailability of carbachol in the iris/ ciliary body (ICB) in nonclinical studies in rabbits, resulting in a more prolonged miotic effect than carbachol alone.7 The peak concentration of carbachol in the ICB in rabbits, measured using liquid chromatography and tandem mass spectrometry, was nearly twice as high 2 hours post dose when combined with brimonidine than when carbachol was dosed on its own (32.8 ng/g vs 17.8 ng/g, P = .159) and the area under the curve (concentration over time) was higher at all time points.7 It remains to be seen how drug penetration and concentration will influence functional outcomes in larger human clinical trials as these combination agents move into phase 3 studies.