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Estimation of Intra-vitreal Half-Lifes in the Rabbit Eye with Semi-mechanistic Equations

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Abstract

Purpose

To develop an alternative method for estimating vitreal half-lifes in the rabbit eye based on simple equations for the physical processes of dissipation and the physiochemical properties of therapeutic substances applied by intravitreal drug administration.

Methods

Equations were derived to describe diffusion in the vitreous humor and permeation through the back-of-the-eye tissue, and the volume of distribution. The model was validated using reported half-life values from 83 compounds collected from literature.

Results

The rate limiting step for dissipation from the vitreous depends mainly on the molecular weight. Dissipation of very low molecular weight (MW) substances (<350 Da) is limited by diffusional transport to the back of the eye, for substances with a MW >350 Da uptake into the back of the eye tissue becomes limiting, and large molecules >500 Da predominantly take an alternative path being cleared through the front of the eye for which diffusion towards the posterior chamber turns out to be limiting. Taking the three rate determining processes into account, the derived model can estimate dissipation rates and respectively vitreal half-life values of small compounds and macromolecules from their molecular weight with very few exceptions.

Conclusions

The equations derived in this analysis provide a simple method to predict vitreal half-lifes for a diverse group of molecules and can be easily implemented in early drug development.

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Abbreviations

A:

Cross section area

BoE:

Back of eye

CFD:

Computational fluid dynamics

D:

Diffusion coefficient

d:

Distance of diffusion path

Da:

Dalton

eta:

Viscosity of the liquid

f:

Fraction

fu:

Fraction unbound

IVT:

Intravitreal

kB :

Boltzmann constant

kdiss :

Dissipation rate

Km:w:

Membrane/water partition coefficient

Ko:w:

Octanol/water partition coefficient

Kp:w:

Protein/water partition coefficient

Kv:w:

Vitreous/water partition coefficient

MW:

Molecular weight

P:

Permeability

PC:

Physicochemical

QSPKR:

Quantitative Structure-Pharmacokinetic Relationships

r:

Radius

R0 :

Hydrodynamic radius of the diffusing particle

T:

Temperature

t1/2 :

Half-life

Vd :

Volume of distribution

Vvit :

Volume of the vitreous

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ACKNOWLEDGMENTS AND DISCLOSURES

The author thanks Anne von Bodman for her writing support. Likewise the critical questions and suggestion of the reviewers are acknowledged, which helped to improve the manuscript very much in a revised version.

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Authors and Affiliations

  1. Clinical Science, Bayer Pharma AG, Wuppertal, Germany

    Walter Schmitt

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  1. Walter Schmitt
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Correspondence to Walter Schmitt.

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Schmitt, W. Estimation of Intra-vitreal Half-Lifes in the Rabbit Eye with Semi-mechanistic Equations. Pharm Res 34, 49–57 (2017). https://doi.org/10.1007/s11095-016-2037-7

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  • DOI: https://doi.org/10.1007/s11095-016-2037-7

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