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J. R. Crison, S. Chaudhuri, V. Lukacova, M. B. Bolger, W. S. Woltosz; Modeling Drug Disposition in Ocular Tissues following Topical Eye Drops and Intravitreal Injection. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5985.
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We have developed a model that describes drug disposition to the anterior and posterior eye tissues.
The model describes the eye as a collection of 8 compartments, including a pre-corneal area (tear film and the conjunctival sac), cornea, conjunctiva, aqueous humor, iris-ciliary body/lens, vitreous humor, retina and choroid/sclera. We assume transport of drug between different compartments to be concentration-gradient driven with rates dependent on physiological (eg. surface area) and drug-dependent physicochemical properties (eg. 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 GastroPlusTM (Simulations Plus, Inc.) 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 optimized to best explain the results from literature studies for two drugs dosed as solutions into two different compartments: pre-corneal area and vitreous humor.
The formulations studied were: a topical clonidine solution (eye drops across two different doses containing 0.06 and 0.12 mg) and an intravitreal injection of voriconazole (0.035 mg). For clonidine, selected model parameters were fitted using in vivo data in six eye compartments for the lower dose. The optimized set of parameters was then used to predict the ocular distribution of clonidine for the higher dose. The predicted concentrations were in a good agreement with the observed concentrations in four eye tissues for which the in vivo data were available. Similarly, the framework of our ocular model was able to provide a good fit to the voriconazole in vivo data across two eye tissues.
Such mechanistic models will be a useful tool for scientists in development of new drug candidates, novel dosage forms and devices with specific release rates, new sites of administration and assessment of toxicological impacts.
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