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- W3176367046 abstract "The discovery of new small-molecule drugs for intravitreal administration would benefit from simple models to predict vitreal clearance (CL). The current models available have limitations in their applicability to small-molecule drugs and translatability to humans. We developed a mechanistic model combining the diffusion rate of the molecule in the vitreous and permeability across posterior segment tissues and applied it to 30 small molecules with observed CL available mostly from literature. We used Caco-2 permeability as a surrogate for ocular tissue permeability. The model predicted rabbit vitreal CL well, with 80% of the predictions being within a 2-fold range of the observed CL. For an accurate prediction, it was crucial to consider the anterior diffusion CL from the vitreous to the aqueous and a limiting diffusion CL for the whole eye. We observed no major differences in model accuracy when using literature permeability values from retinal pigment epithelial cell models. Importantly, by adopting the specific dimensions of the human eye, the model was able to accurately predict vitreal CL of four compounds for which human vitreal CL data are available. In summary, this mechanistic model enables a simple, accurate, and translatable estimation of small-molecule vitreal CL." @default.
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- W3176367046 date "2021-06-21" @default.
- W3176367046 modified "2023-10-12" @default.
- W3176367046 title "Mechanistic Model for the Prediction of Small-Molecule Vitreal Clearance Combining Diffusion-Limited and Permeability-Limited Clearance" @default.
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- W3176367046 doi "https://doi.org/10.1021/acs.molpharmaceut.1c00236" @default.
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