Abstract

Purpose: Development of generic formulations of ophthalmic corticosteroids and regulatory acceptance of bioequivalence can be facilitated by analysis of the mechanisms of ocular dissolution, absorption, distribution, and elimination. For this purpose we developed an in silico ocular PBPK model for fluorometholone (FML), a commonly preferred ophthalmic corticosteroid.

Methods: The Ocular Compartmental Absorption and Transit™ (OCAT™) model within GastroPlus 9.0 was used to build a mechanistic compartmental model to account for extraocular loss of the administered dose, dissolution, ocular absorption, and distribution in the albino rabbit eye. Due to the lack of literature data for intravenous and oral delivery of FML, we built a systemic distribution and clearance model using biopharmaceutical properties estimated by ADMET Predictor™ 7.1. We used experimental permeability for cornea (Hull, 2002). Permeability for conjunctiva, aqueous humor, and iris-ciliary body, and systemic elimination rate for iris-ciliary body, were fitted to match the observed aqueous humor concentrations for the saturated solution dose. The OCAT model simulation results for FML administered as a 0.1% suspension were then compared to the experimental aqueous humor concentrations reported in the literature (Sieg, 1975). Particle size sensitivity analysis was also performed.

GTC Bio Ocular Diseases Drug Discovery, March 19-20, 2015, San Diego, CA

By Michael B. Bolger, Jessica Spires, James M. Mullin, Joyce Macwan, Jayeeta Ghosh, and Viera Lukacova