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

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Abstract

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 retina 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 62–100 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.

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Abbreviations

2D/3D:

Two/three-dimensional

AH:

Aqueous humor

AMD:

Age-related macular degeneration

ATM :

Amount of macromolecule eliminated through trabecular meshwork with aqueous drainage

AUCa :

Area under the concentration curve in the aqueous humor

Ca :

Mean concentration of macromolecule in the aqueous humor (anterior chamber)

CFD :

Computational fluid dynamics

Cv :

Mean concentration of macromolecule in the vitreous

D:

Diffusion coefficient of macromolecule in water

Dret :

Apparent diffusion coefficient of macromolecule in retina

f:

Aqueous humor flow rate

FEM:

Finite element modeling

IC:

Intracameral

IOP :

Intraocular pressure

IVT:

Intravitreal

kac :

Elimination rate constant of macromolecule from the anterior chamber

kv :

Elimination rate constant of macromolecule from the vitreous

MRI:

Magnetic resonance imaging

MW:

Molecular weight

Papp :

Apparent permeability coefficient of macromolecule in membrane

PK:

Pharmacokinetics

rH :

Hydrodynamic radius

RPE:

Retinal pigment epithelium

t1/2 :

Elimination half-life

TM :

Trabecular meshwork

Va :

Volume of the anterior chamber

Vv :

Volume of the vitreous

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Authors and Affiliations

  1. School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210, Kuopio, Finland

    Marko Lamminsalo, Ella Taskinen, Arto Urtti & Veli-Pekka Ranta

  2. Comsol Oy, Helsinki, Finland

    Timo Karvinen

  3. Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark

    Astrid Subrizi

  4. Department of Chemistry and Materials Science, Aalto University, Espoo, Finland

    Lasse Murtomäki

  5. Faculty of Pharmacy, Drug Research Program, University of Helsinki, Helsinki, Finland

    Arto Urtti

  6. St Petersburg State University, Petergoff, St. Petersburg, Russian Federation

    Arto Urtti

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  1. Marko Lamminsalo
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Correspondence to Marko Lamminsalo.

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Lamminsalo, M., Taskinen, E., Karvinen, T. et al. Extended Pharmacokinetic Model of the Rabbit Eye for Intravitreal and Intracameral Injections of Macromolecules: Quantitative Analysis of Anterior and Posterior Elimination Pathways. Pharm Res 35, 153 (2018). https://doi.org/10.1007/s11095-018-2435-0

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