Modeling of corneal and retinal pharmacokinetics after periocular drug administration

• Type of Material: Article
• Authors: Aniruddha C. Amrite, University of Nebraska; Henry F. Edelhauser, Emory University; Uday B. Kompella, University of Nebraska
• Language: English
• Date: 2008-01-01
• Publisher: Association for Research in Vision and Ophthalmology (ARVO)
• Publication Version: Final Published Version
• Copyright Statement: Copyright © Association for Research in Vision and Ophthalmology.
• Final Published Version (URL): http://dx.doi.org/10.1167/iovs.07-0593
• Title of Journal or Parent Work: Investigative Ophthalmology & Visual Science
• ISSN: 0146-0404
• Volume: 49
• Issue: 1
• Start Page: 320
• End Page: 332
• Grant/Funding Information: Supported by an unrestricted research gift from Pfizer Global Research and by National Eye Institute Grants R24 EY017045, R01 DK064172, R03 EY013842, and R21 EY017360.
• Keywords: BLOOD-FLOW; RABBIT EYE; SUB-CONJUNCTIVAL; Ophthalmology; Life Sciences & Biomedicine; EPISCLERAL CYCLOSPORINE IMPLANT; ANECORTAVE ACETATE; DELIVERY; SUBCONJUNCTIVAL INJECTION; HYDROGEN CLEARANCE; POSTERIOR SEGMENT; CHOROIDAL NEOVASCULARIZATION; Science & Technology
• Research Categories: Health Sciences, Opthamology; Chemistry, Pharmaceutical

Abstract

PURPOSE. To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. METHODS. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. RESULTS. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal tmax. Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed. CONCLUSIONS. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.