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, 49 (1), 320-32

Modeling of Corneal and Retinal Pharmacokinetics After Periocular Drug Administration

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Modeling of Corneal and Retinal Pharmacokinetics After Periocular Drug Administration

Aniruddha C Amrite et al. Invest Ophthalmol Vis Sci.

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 t(max). 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.

Figures

Figure 1
Figure 1
Model-predicted and observed concentrations of celecoxib in the cornea after administration of 3 mg celecoxib by periocular injection to BN rats. (A) Two-compartment model. (B) Three-compartment model with a distribution compartment for the cornea. (C) Three-compartment model with a dissolution step included for the suspension formulations. (D) Four-compartment model with a distribution compartment for the cornea, and a dissolution/release step included for the suspension formulation. (E) Three-compartment model with a dissolution/release step for suspension formulation and initial value in the cornea estimated as a parameter. Lighter arrow: leak-back to the cornea from the site of administration after periocular injection. (F) Four-compartment model with a distribution compartment for the cornea, dissolution/release step for the suspension formulation, and initial concentration in the cornea estimated as a separate parameter. Lighter arrow: leak-back to the cornea. (G) Four-compartment model with a distribution compartment for the cornea, dissolution/release step for the formulation, and elimination from the distribution compartment. (H) Four-compartment model with a distribution compartment for the cornea, dissolution/release step for the formulation, and elimination from the distribution compartment and the initial concentration in the cornea estimated as a separate parameter. Lighter arrow: leak-back to the cornea. The model in (E) was selected as the finalized model. K10, elimination rate constant from the periocular site; K12, absorption rate constant for the cornea; K20, elimination rate constant from the cornea; K23, rate constant for transfer of drug from the cornea to the distribution compartment; K32, rate constant for transfer of drug from the distribution compartment to the cornea; K30, elimination rate constant from the distribution compartment; Krel, release/dissolution rate constant for the dissolution of the drug from the formulation. The observed data are expressed as the mean ± SD for n = 4.
Figure 2
Figure 2
Validation of the corneal pharmacokinetics model described in Figure 1E by using the data of Ayalasomayajula and Kompella for celecoxib periocular administration in SD rats. Inset: finalized structural model developed from using the celecoxib pharmacokinetics data in BN rats by Cheruvu et al. The data predicted from the finalized model was compared to the data obtained by Ayalasomayajula et al. A very good correlation was obtained between the model-predicted and experimentally observed values. The observed data are expressed as the mean ± SD for n = 3.
Figure 3
Figure 3
Validation of the corneal pharmacokinetics model described in Figure 4 by using the data of Tsuji et al. for subconjunctival administration of prednisolone in rabbits. The prednisolone data was fit to the model by curve fitting. The observed data are expressed as the mean ± SEM for n = 3–9. Excellent correlation was found between the observed and the model-predicted data.
Figure 4
Figure 4
Simulation of celecoxib drug levels in the cornea of BN rats by using the parameter estimates in Table 1 and the model in Figure 1E, after administration of 3 mg celecoxib by the periocular route as a solution, suspension, or sustained-release system. The sustained-release system was assumed to have a release rate 1000 times less than the release from suspension. Top: structural model; inset: simulated corneal levels of celecoxib during the initial 12 hours after solution and suspension administration.
Figure 5
Figure 5
Model-predicted and observed concentrations of celecoxib in the retina after administration of 3 mg celecoxib by periocular injection to BN rats. (A) Two-compartment model. (B) Three-compartment model with a distribution compartment to the retina. (C) Three-compartment model with a dissolution/release step included for the suspension formulations. (D) Four-compartment model with a distribution compartment for the retina and a dissolution/release step included for the suspension formulation. (E) Five-compartment model with a transfer compartment representing the sclera-choroid-RPE, a distribution compartment to the retina and a dissolution/release step included for the suspension formulation. (F) Five-compartment model with a transfer compartment representing the sclera-choroid-RPE, a distribution compartment to the retina, no retinal elimination and a dissolution/release step included for the suspension formulation. The model in (E) was selected as the finalized model to describe retinal pharmacokinetics after periocular administration. (A–D) K10, elimination rate constant from the periocular tissue; K12, absorption rate constant for the retina; K20, elimination rate constant for the retina; K23, rate constant for transfer of drug from the retina into the distribution compartment; K32, rate constant for transfer of drug from the distribution compartment to the retina; Krel, rate constant for dissolution/release of celecoxib from the formulation. (E, F) K10, elimination rate constant for periocular site; K12, absorption rate constant for sclerachoroid-RPE (transfer compartment). K20, elimination rate constant for sclera-choroid-RPE; K23, transfer constant to the retina from the sclerachoroid-RPE; K32, transfer constant for the sclera-choroid-RPE from the retina; K30, elimination rate constant from the retina; K34, rate constant for transfer of drug from the retina into the distribution compartment; K43, rate constant for transfer of drug from the distribution compartment into the retina; Krel, rate constant for dissolution/release of celecoxib from the formulation. The observed data are expressed as the mean ± SD for n = 4.
Figure 6
Figure 6
Model-predicted and observed concentrations of celecoxib in the retina after administration of 3 mg celecoxib by periocular injection to BN rats using the recirculation models. (A) Four-compartment model with dissolution/release step for the formulation and inclusion of a circulation compartment. (B) Five-compartment model with dissolution/release step for the formulation, a distribution compartment for the retina, and inclusion of a circulation compartment. (C) Six-compartment model with dissolution/release step for the formulation, a distribution compartment for the retina and inclusion of a circulation compartment and a transfer compartment representing the sclera-choroid-RPE. (D) Six-compartment model with dissolution/release step for the formulation, a distribution compartment for the retina and inclusion of a circulation compartment and a transfer compartment representing the sclera-choroid-RPE with no elimination from the retina. (A, B) K10, transfer constant for transfer of drug from the periocular site to the circulation; K01, transfer constant for transfer of the drug from the circulation to the periocular site; K12, absorption rate constant for retina; K20, rate constant for transfer of the drug from the retina to the circulation compartment; K02, rate constant for transfer of the drug from the circulation compartment to the retina; K23, rate constant for transfer of the drug from the retina to the distribution compartment; K32, rate constant for transfer of drug from the distribution compartment to the retina; Kel, elimination rate constant from the circulation; Krel, rate constant for dissolution/release from the formulation. (C, D) K10, transfer constant for transfer of drug from the periocular site to the circulation; K01, transfer constant for transfer of the drug from the circulation to the periocular site; K12, absorption rate constant for sclera-choroid-RPE; K20, rate constant for transfer of the drug from the sclera-choroid-RPE to the circulation compartment; K02, rate constant for transfer of the drug from the circulation compartment to the sclera-choroid-RPE; K23, rate constant for absorption of drug into the retina from the sclera-choroid-RPE; K32, rate constant for transfer of drug from the retina to the sclera-choroid-RPE; K30, rate constant for transfer of drug from the retina to the circulation compartment; K03, rate constant for the transfer of drug from the circulation compartment to the retina; K34, rate constant for transfer of drug from the retina to the distribution compartment; K43, rate constant for transfer of rug from the distribution compartment to the retina; Kel, elimination rate constant from the circulation; Krel, rate constant for dissolution/release from the formulation. The observed data are expressed as the mean ± SD for n = 4.
Figure 7
Figure 7
Model-predicted and observed concentrations of celecoxib in the retina after administration of 3 mg celecoxib by periocular injection to SD (nonpigmented) rats. The data were fit to the finalized model selected for retinal kinetics and shown in Figure 5E. Excellent correlation was found between the predicted and observed data. The observed data are expressed as the mean ± SD for n = 3.
Figure 8
Figure 8
Simulation of celecoxib drug levels in the retina of BN rats by using the parameter estimates in Table 4 and the model in Figure 5E after administration of 3 mg celecoxib by the periocular route as a solution, suspension, or sustained-release system. The sustained-release system was assumed to have a release rate 1000 times less than the release from suspension. Top: structural model; inset: simulated retinal levels of celecoxib during the initial 12 hours after solution and suspension administration.

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