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Gerhard Garhofer, Martin Kallab, Kornelia Schutzenberger, Bhavapriya Schäfer, Aimin Tan, Phatsawee Jansook, Markus Zeitlinger, Laura Lorenzo-Soler, Einar Stefánsson; Pharmacokinetics and Local Tolerability of Cyclodextrin-based Angiotensin-Receptor Antagonist eye drops in rabbits. Invest. Ophthalmol. Vis. Sci. 2020;61(7):32.
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© ARVO (1962-2015); The Authors (2016-present)
Cyclodextrin nanoparticles have been shown to increase bioavailability of poorly water-soluble drugs and may therefore serve as an option for drug delivery to the back of the eye. The current study was performed to investigate the ocular pharmacokinetics (PK) and local tolerability of the two newly developed γ-cyclodextrin based angiotensin receptor antagonist formulations , cyclodextrin-irbesartan 1.5% and cyclodextrin-candesartan 0.15%.
59 rabbits were included in the PK study. For both drugs, single and multiple dose PK were performed: Single dose rabbits (n=49) were euthanized 0.5, 1.5, 3, 6 or 12 hours-post dose, whereas multiple dose animals (n=10) were dosed for 5 days twice daily before euthanisation. Analysis was done using LC-MS/MS. PK parameters including maximal drug concentration (Cmax) and time of maximal drug concentrations (Tmax) were calculated for aqueous humor (AH) and retinal tissue/choroid (RT). Local tolerability of cyclodextrin-irbesartan 1.5% eye drops was assessed using a modified Draize scale after twice daily administration for 28 days in a different group of 5 animals.
Single dose irbesartan administration led to a RT Cmax of 251±143ng/g at 0.5 hours whereas in the AH a Cmaxof 121±69ng/g was reached at 3 hours post instillation. For single dose candesartan, RT Cmax was 63±39ng/g at 0.5 hours after application. AH reached a Cmax of 30±14ng/g at the 3 hours time point for candesartan. For multiple dosing mean RT concentration reached 338±124ng/g for irbesartan and 36±10ng/g for candesartan, whereas mean AH concentrations were 231±68ng/g and 70±22ng/g, respectively. Local tolerability during the 28 day treatment period was good.
The present data shows good local tolerability and high tissue concentration in the retina, showing the potential of cyclodextrin nanoparticles for drug delivery to the posterior pole of the eye.
This is a 2020 ARVO Annual Meeting abstract.
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