Modeling of corneal and retinal pharmacokinetics after periocular drug administration.

Drug delivery by the topical route, although effective for anterior segment disorders, does not result in significant retinal concentrations of most molecules.1 Because it is a safer approach, the periocular route of drug delivery is gaining importance as an alternative to the intravitreous route for the treatment of posterior segment ocular disorders. The periocular routes include the subconjunctival, subtenon, peribulbar, and retrobulbar modes.2 Although these routes deliver drugs to the posterior segment tissues including the retina and the vitreous, the bioavailability of the route is not clearly established. Literature on the pharmacokinetics of periocular injections is relatively sparse compared with that on the topical or intravitreous modes of administration. Understanding the pharmacokinetics is essential for determining the dose regimen and for designing novel drugs and delivery systems. Pharmacokinetic modeling is a powerful tool for a better understanding of drug disposition. There have been some attempts to perform mathematical modeling of periocular injections. These approaches for posterior segment delivery have been summarized by Pekka-Ranta and Urtii.3 Tsuji et al.4 described the pharmacokinetics of a small lipophilic steroid (prednisolone) in tissues of the anterior and posterior segments. However, the model development procedure was not described, and there were no statistical goodness-of-fit criteria mentioned, and thus the use of their model is limited. Lee and Robinson5 developed a model that describes the pharmacokinetics in the vitreous after periocular administration.5 The model was developed with the data of Tsuji et al.4 Most of the posterior segment disorders affect the retina and/or the choroid, and no model has been developed to date to describe the pharmacokinetics of the drugs in the retina. There is significant drug delivery to the anterior segment after subconjunctival administration.6 – 8 However, attempts to model the pharmacokinetics of drugs in the cornea after subconjunctival or other periocular modes of administration have been few. Modeling software is an important consideration in developing any mathematical model. Berkeley Madonna (Berkeley Madonna, Berkeley, CA) is a commercially available modeling software that numerically solves ordinary differential equations. It has a user friendly graphic user interface (GUI) and the users can modify the model by diagrammatic modification. Differential equations are directly developed and solved by the software (www.berkeleymadonna.com/BM%20User's%20Guide%208.0.pdf). The software has powerful algorithms for achieving convergence and has been used extensively in the development of multicompartment, multiparametric models such as physiologically based pharmacokinetics models (PBPK).9,10 The modeling software allows for both the forward-modeling approach (simulation) and backward-modeling approaches (parameter estimations using curve fitting). Thus, the purpose of this study was to use Berkeley Madonna and the compartment approach to pharmacokinetic modeling, to explain the pharmacokinetics of small lipophilic molecules in the cornea and retina after periocular administration.