Ocular Delivery of the Novel Spleen Tyrosine Kinase Inhibitor R406 for Retinoblastoma

Abstract

 

Purpose

 

Drug delivery to the eye remains a major challenge due to limited blood retinal barrier (BRB) penetration and systemic side-effects. Local administration routes represent a promising potential solution, but unfortunately relatively little is known about the relationship between compound properties and in vivo ocular pharmacokinetics. R406 is an inhibitor of a spleen tyrosine kinase (SYK), which was recently identified as a novel therapeutic target for retinoblastoma. Our objective was to investigate the effects of formulation, administration site and physical-chemical compound properties on ocular and systemic R406 pharmacokinetics.

 

Methods

 

Systemic and intraocular pharmacokinetics were evaluated in mice for various formulations of three forms of R406 with varying compound properties (R406 free base, R406 phenylsulfonate salt, and the phosphate prodrug of R406, R788) after single dose subconjunctival administration. PK of orally administered R788 was also characterized.

 

Results

 

Tmax occurs at 0.5 hr for all formulations and routes tested, indicating rapid absorption of R406 into the eye. Local subconjunctival delivery of R788 increases vitreous exposure and decreases systemic exposure compared with R788 administered orally. At comparable doses, R788 in cosolvent solution achieves a maximum vitreous concentration 5.7-fold higher than the water insoluble R406 free base in emulsion, which suggests aqueous solubility impacts ocular penetration. In contrast, R788 administered in suspension exhibits a lower vitreous AUC and higher systemic exposure than the less water soluble R406 salt administered in DMSO, which suggests that at higher doses the more water soluble prodrug diffuses more readily from the injection site into systemic circulation.

 

Conclusions

 

Administration site, compound properties and formulation impact ocular and systemic pharmacokinetics. Our results inform our understanding of R406 administration and the design and formulation of ocular therapeutics in general.

 

 

Concentration versus time plots of plasma (top) and vitreous (bottom) exposure following systemic (oral, squares) and local (subconjunctival injection, circles) administration of R788

 

 

Formulation details and vitreous pharmacokinetic parameters for R406 formulations investigated including AUC (area under the concentration-time curve), Cmax (maximum concentration) and tmax (time Cmax observed)

 

Keywords: 703 retinoblastoma