Abstract

Introduction: The purpose of this study was to model the ocular absorption, distribution and clearance of clonidine and voriconazole from topical and intravitreal applications, respectively. Clonidine is a potent hypotensive agent used to lower intra-ocular pressure (IOP) in the treatment of Glaucoma [1]. Voriconazole has been known to provide for a treatment for post-operative fungal endophthalmitis [2].

Methodology: Our model describes the eye as a collection of 8 compartments, including a precorneal area (tear film and the conjunctival sac), cornea, conjunctiva, aqueous humor, iris-ciliary body/lens, vitreous humor, retina and choroid/sclera. The passive diffusion of drugs between different compartments is assumed to be concentration-gradient driven with rates dependent on physiological (e.g. surface area) and drug-dependent physicochemical properties (e.g.permeability) for each compartment. Mechanisms such as nasolacrimal drainage (through tear flow and volumetric drainage), ocular metabolism, melanin binding etc. have also been incorporated into this model. The ocular model is connected to the pharmacokinetic model in GastroPlus™ (Simulations Plus, Inc.) [3] to allow for simulation of drug appearance in plasma after ocular administration as well as drug uptake by the eye tissues after oral or systemic administration. Simulation parameters were fitted to best explain the results from literature studies for two drugs dosed as solutions into two different compartments: precorneal area and vitreous humor. The formulations studied were: a topical clonidine solution (eye drops dosed at 0.06 and 0.12 mg) [4] and an intravitreal injection of voriconazole (0.035 mg) [5]. For clonidine, selected model parameters (relevant ocular permeabilities, volumetric drainage constant and tear flow rate) were fitted using in vivo data from rabbit in six eye compartments for the lower dose. The fitted set of parameters was then used to predict the ocular distribution of clonidine for the higher dose. A similar framework was used to fit a model for intravitreal administration of voriconazole for which data were available for only one dose.

Association for Research in Vision and Ophthalmology (ARVO) 2009 Annual Meeting, May 3-7, 2009, Fort Lauderdale, FL

By S. Ray Chaudhuri, J.R. Crison, Viera Lukacova, Michael B. Bolger, Walter S. Woltosz