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S. S.-H. Lee, D. Z. D'Argenio, R. A. Moats, J.-E. Lin, D. F. Welty, P. Hughes, S. M. Whitcup, M. R. Robinson; Pharmacokinetic Modeling to Improve the Design of Intravitreal Corticosteroid Implants for Treating Macular Edema. Invest. Ophthalmol. Vis. Sci. 2007;48(13):288.
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Sustained-release corticosteroid implants have been shown to be effective for treating macular edema from diabetic retinopathy, venous occlusive disease, and uveitis. Unfortunately, drug exposure to the anterior segment leads to myocilin accumulation in the trabecular meshwork cells leading to elevation of the IOP. A number of corticosteroid-releasing implants deliver drug from the pars plana region, directly adjacent to the trabecular meshwork, approximately 18 to 20 mm away from the macula. We modeled the previously published pharmacokinetic data from a fluocinolone acetonide 0.5 mg implant (Driot et al. J Ocular Pharm & Therap 2004;20:269) to evaluate the efficiency of drug delivery to the macula from an implant in the pars plana region
A pharmacokinetics model was developed using Fick’s 2nd law , C(x,t)= C0*erfc[x/2*sqrt(Dt)], to predict drug concentrations, C, a given distance (x) from the implant C0. A summated diffusion coefficient was determined with previously published ocular drug distribution data. C0 was the maximum solubility of the drug at physiologic conditions, and C was the concentration of drug a given distance x from either the aqueous humor or the macula.
The summated diffusion coefficients from the implant to the aqueous humor and the implant to the macula were 7.20E-09 and 2.64E-07, respectively. At steady state concentration, 13 days post-implantation, with the implant located at the pars plana (i.e. 5 mm from the anterior chamber and 20 mm from the macula), the concentrations in the aqueous humor and macula were calculated to be 0.0008 ug/ml, and 0.0899 ug/g, respectively. In the model, a virtual implant was moved closer to the macula (i.e. 6.4 mm from the anterior chamber and 16 mm away from the macula) and the concentrations in the aqueous humor were > 4 fold less and the macula concentrations increased to 0.36 ug/g. The drug concentration at the macula increased exponentially increasing to 2.8 ug/g when the virtual implant was 8 mm from the macula.
Assuming the goal of a corticosteroid-releasing implant for macular edema is to minimize anterior segment exposure and maximize macular drug concentrations, our modeling results suggest that a pars plana location is not ideal. More posteriorly placed implants in the vitreous would be more efficient in treating macular edema.
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