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

• Published in: Pharmaceutical research 2017, Vol.34 (1), p.49-57
• Main Author: Schmitt, Walter
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Diffusion; Eyes & eyesight; Half-Life; Macromolecular Substances - administration & dosage; Macromolecular Substances - metabolism; Medical Law; Molecular Weight; Permeability; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - metabolism; Pharmaceuticals; Pharmacology; Pharmacology/Toxicology; Pharmacy; Rabbits; Research Paper; Small Molecule Libraries - administration & dosage; Small Molecule Libraries - metabolism; Vitreous Body - metabolism
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-016-2037-7

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 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.