Extended Pharmacokinetic Model of the Intravitreal Injections of Macromolecules in Rabbits. Part 2: Parameter Estimation
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RESEARCH PAPER
Extended Pharmacokinetic Model of the Intravitreal Injections of Macromolecules in Rabbits. Part 2: Parameter Estimation Based on Concentration Dynamics in the Vitreous, Retina, and Aqueous Humor Marko Lamminsalo 1
&
Timo Karvinen 2 & Astrid Subrizi 1 & Arto Urtti 1,3,4 & Veli-Pekka Ranta 1
Received: 15 June 2020 / Accepted: 5 October 2020 # The Author(s) 2020
ABSTRACT Purpose To estimate the diffusion coefficients of an IgG antibody (150 kDa) and its antigen-binding fragment (Fab; 50 kDa) in the neural retina (Dret) and the combined retinal pigment epithelium-choroid (DRPE-cho) with a 3-dimensional (3D) ocular pharmacokinetic (PK) model of the rabbit eye. Methods Vitreous, retina, and aqueous humor concentrations of IgG and Fab after intravitreal injection in rabbits were taken from Gadkar et al. (2015). A least-squares method was used to estimate Dret and DRPE-cho with the 3D finite element model where mass transport was defined with diffusion and convection. Different intraocular pressures (IOP), initial distribution volumes (Vinit), and neural retina/vitreous partition coefficients (Kret/vit) were tested. Sensitivity analysis was performed for the final model. Results With the final IgG model (IOP 10.1 Torr, Vinit 400 μl, Kret/vit 0.5), the estimated Dret and DRPE-cho were 36.8 × 10−9 cm2s−1 and 4.11 × 10−9 cm2s−1, respectively, and 76% of the dose was eliminated via the anterior chamber. Modeling of Fab revealed that a physiological model parameter “aqueous humor formation rate” sets constraints that need to be considered in the parameter estimation.
Conclusions This study extends the use of 3D ocular PK models for parameter estimation using simultaneously macromolecule concentrations in three ocular tissues.
KEY WORDS computational fluid dynamics . intravitreal injection . macromolecule . Ocular pharmacokinetics . permeability
ABBREVIATIONS 2D/ 3D AH AMD AUC Ccalc,t CFD Cobs,t Dret
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02946-1) contains supplementary material, which is available to authorized users. * Marko Lamminsalo [email protected]
1
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland
2
Granlund Consulting Oy, Helsinki, Finland
3
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
4
Laboratory of Biohybrid Technologies, Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russian Federation
DRPEcho
Dvit Dwat Fab FEM IgG ILM IOP IVT Kret/vit
Two/three-dimensional Aqueous humor Age-related macular degeneration Area under the curve Calculated mean concentration of macromolecule in corresponding domain at time t Computational fluid dynamics Observed mean concentration of macromolecule in corresponding domain at time t Diffusion coefficient of macromolecule in neural retina (cm2 s−1) Diffusion coefficient of macromolecule in retinal pigment epithelium-choroid (cm2 s−1)
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