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Dec 3, 2009
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Modeling Drug Disposition of Timolol in Ocular Tissues of Rabbit following Topical Eye Drops

Abstract

Introduction: Recently, we reported the successful application of a novel mathematical model describing drug disposition in eye compartments to simulate disposition of clonidine after topical (eye drop) administration [1]. This example extends the methodology to describe the disposition of timolol in different eye tissues and plasma after topical administration. Timolol is a nonselective beta-adrenoceptor antagonist used to lower intraocular pressure (IOP) [2]. A serious disadvantage of ocular timolol therapy is the amount of drug getting into systemic circulation that adversely affects vital organ functions in elderly patients [2]

Methodology: The ocular model used in this study is identical to the internally-developed model used earlier in Ray Chaudhuri et al. [1]. It describes the eye as a collection of multiple compartments with transport of drugs between compartments modeled by concentration-gradient driven passive diffusion with rates dependent on physiological (e.g. surface area) and drug-dependent physicochemical properties (e.g. permeability) for each compartment. Mechanisms critical to topical delivery such as nasolacrimal drainage (through tear flow and volumetric drainage) 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. The formulation studied was topical timolol solution, across two distinct research groups [4-5]. The PKPlus™ module of GastroPlus was used to fit systemic PK parameters from observed plasma profiles after intravenous (IV) administration in rabbits [4] and was used to simulate plasma profiles from ocular administration. Lee et al. [4] also reported concentration-time profiles in different ocular tissues from a topical dose, which were used to optimize selected ocular parameters (relevant ocular permeabilities and tear flow rate). The fitted set of parameters was then used to predict the observed concentration-time profiles in three ocular tissues, as reported in Francoeur et al., with a formulation and dose identical to that used in [4].

8th International Symposium on Ocular Pharmacology and Therapeutics (ISOPT), December 3-6, 2009, Rome, Italy

By S. Ray Chaudhuri, Viera Lukacova, Walter S. Woltosz

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