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Hermann Russ, Andreas Gravius, Nico Wegener, Alexander Gebauer; Ocular and Systemic Distribution of the Developmental Glaucoma and Dry AMD drug MRZ-99030 in Pigmented Mouse, Rat, Rabbit, and Non-Human Primate. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1959.
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The ocular tissue distribution and systemic pharmacokinetics of MRZ-99030 was determined after single or repeated topical ocular dose regimens of MRZ-99030 eye drops in pigmented mice, rats, rabbits, and non-human primates. MRZ-99030, an Aβ aggregation modulator, is currently under development for neuroprotective treatment of glaucoma and dry age related macular degeneration (AMD) which are the leading causes of blindness and representing diseases with a high unmet medical need.
Dutch Belted rabbits, Cynomolgus monkeys, Dark Agouti rats, and C57/BL6 mice received single or repeated bilateral topical ocular doses of MRZ-99030 eye drops. Ocular tissues (aqueous humor, bulbar conjunctiva, choroid with retinal pigmented epithelium (RPE), cornea, iris-ciliary body, optic nerve, retina, and vitreous humor) and plasma were collected up to 24h after dosing and analyzed for MRZ-99030 by liquid chromatography-mass spectrometry (LC-MS).
MRZ-99030 was readily absorbed into ocular tissues for all species with the highest concentrations observed in the cornea and conjunctiva. MRZ-99030 was also found in the ocular tissues of the posterior segment (choroid with retinal pigment epithelium and retina) at all time points. MRZ-99030 could be detected in all ocular tissues and also systemically. Pharmacokinetic analysis revealed elimination half-lives that indicate somewhat sustained concentrations in melanin containing tissues. Concentrations in ocular tissues, in particular for the retina, increase with an increase in dose level (mouse and rat) and dose frequency (all species) and are above the affinity to Aβ.
The results show that MRZ-99030 is absorbed into the ocular tissues in all species following topical administration and is readily distributed to the posterior segment of the eye, including the retina. Therefore, this finding strongly supports that MRZ-99030 applied as eye drops is able to modulate the Aβ aggregation in the target tissue of glaucoma and AMD.
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