Abstract
Purpose :
Eye-drop drugs are preferrable as a non-invasive and less treatment burden procedure compared to the current intravitreal injection drugs. However, insufficient drug exposure in posterior eye segment is considered as a major issue of eye-drop drugs to achieve drug efficacy. Tivozanib, a potent approved vascular endothelial growth factor receptor inhibitor, is nano-crystalized and is in clinical development as an eye drop for treatment of neovascular age-related macular degeneration (nAMD) and macular edema. This study aimed to assess ocular pharmacokinetics of tivozanib eye drop in rabbits and its anti-angiogenic efficacy in laser-induced choroidal neovascularization (CNV) model in monkeys.
Methods :
We compared the ocular tissue distribution after ocular instillation of tivozanib eye drops in pigmented and albino rabbits, as well as nanocrystal and microcrystal formulations. We instilled nano-crystallized tivozanib (nTivo) eye drops ocularly for 3 weeks in a laser-induced CNV model in cynomolgus monkeys and evaluated its anti-angiogenic efficacy and distribution in the choroid and retina.
Results :
In pigmented rabbits, nTivo eye drops showed up to 9.5 times higher drug delivery efficiency to the retina/choroid compared to microcrystal formulations. Repeated ocular instillation of nTivo eye drops increased exposure in the retina/choroid (4.6-fold) compared to single ocular instillation in pigmented rabbits. The elimination half-life (t1/2) of tivozanib was longer in the retina/choroid (247.5 hours) compared to serum (49.7 hours). Pigmented rabbits showed higher exposure (3.2-fold) and longer t1/2 in the retina/choroid compared to albino rabbits. In monkey CNV models, nTivo eye drops decreased neovascularization lesion area and showed increased drug concentrations in the choroid and retina with higher dosing frequency.
Conclusions :
Our in vivo data suggest that nTivo eye drops could be a potential therapeutic agent for treating posterior eye diseases. The accumulation and sustained exposure to tivozanib in the choroid and retina, which may contribute to the efficacy in retinal vascular disease, may have resulted from its innate melanin-binding properties and nano-crystallized formulation of tivozanib.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.