Extended Pharmacokinetic Model of the Rabbit Eye for Intravitreal and Intracameral Injections of Macromolecules: Quantitative Analysis of Anterior and Posterior Elimination Pathways

Marko Lamminsalo, Ella Taskinen, Timo Karvinen, Astrid Subrizi, Lasse Murtomäki, Arto Urtti, Veli-Pekka Ranta
2018 Pharmaceutical Research  
Purpose To extend the physiological features of the anatomically accurate model of the rabbit eye for intravitreal (IVT) and intracameral (IC) injections of macromolecules. Methods The computational fluid dynamic model of the rabbit eye by Missel (2012) was extended by enhancing the mixing in the anterior chamber with thermal gradient, heat transfer and gravity, and studying its effect on IC injections of hyaluronic acids. In IVT injections of FITC-dextrans (MW 10-157 kDa) the diffusion though
more » ... etina was defined based on published in vitro data. Systematic changes in retinal permeability and convective transport were made, and the percentages of anterior and posterior elimination pathways were quantified. Simulations were compared with published in vivo data. Results With the enhanced mixing the elimination half-lives of hyaluronic acids after IC injection were 61-99 min that are similar to in vivo data and close to the theoretical value for the well-stirred anterior chamber (57 min). In IVT injections of FITC-dextrans a good match between simulations and in vivo data was obtained when the percentage of anterior elimination pathway was over 80%. Conclusions The simulations with the extended model closely resemble in vivo pharmacokinetics, and the model is a valuable tool for data interpretation and predictions. KEY WORDS (max 5) ocular pharmacokinetics, intravitreal injection, intracameral injection, computational fluid dynamics, macromolecule ABBREVIATIONS ATM amount of macromolecule eliminated through trabecular meshwork with aqueous drainage AH aqueous humor AMD age-related macular degeneration AUCa area under the concentration curve in the aqueous humor Ca mean concentration of macromolecule in the aqueous humor (anterior chamber) Cv mean concentration of macromolecule in the vitreous CFD computational fluid dynamics Vv volume of the vitreous
doi:10.1007/s11095-018-2435-0 pmid:29855726 fatcat:squpfrl3enbpzptomkvbeilsta