Figure 17 Finite element modeling of concentration profiles established after central intravitreal bolus injection, using FIDAP, 3D geometric model for the posterior rabbit eye, similar to Ref. 247, comprising the vitreous region, the retina, choroid, and sclera. At time zero, a spherical bolus of drug having unit concentration was placed in the center, behind the lens. (A) Contours of drug concentration simulated six hours after injection, assuming a reasonable value (250) for the diffusion coefficient (6 x 10-6 cm2/sec) and efficient clearance by the choroid. Permeability across the lens and hyloid membrane is assumed to be negligible. (B) Simulated concentration profile two days after injection of FITC-dextran (diffusion coefficient 6 x 10-7 cm2/sec), assuming zero retinal permeability and hyloid permeability 8 x 10-5 cm/sec. Drug partition coefficients in the vitreous, retina, choroid, and sclera were assumed to be roughly 1, 4, 4, and 2, respectively.

subconjunctival, sub-Tenon's, or retrobulbar injection, can be a reasonable alternative for delivering some drugs to the posterior segment (198).

Subconjunctival administration In addition to being less invasive compared with intravitreal injection, subconjunctival injection can be well suited to drug depots for prolonging the duration of drug therapy. Furthermore, subconjunctival administration may avoid much of the toxicity encountered with systemic administration, with drug concentrations in the eye typically substantially higher and systemic levels lower following subconjunctival versus systemic administration. For example, following

Figure 18 Finite element modeling of steady-state concentration profiles in the human eye (247) from a hypothetical device that releases drug toward the front of the eye, for a low-molecular-weight drug that is efficiently eliminated through the retina. Solid contours represent changes of 1 log unit with the eye under zero pressure. Dashed contours show the influence of the normotensive 5 mmHg intraocular pressure difference between the ocular interior and the episclera.

Figure 18 Finite element modeling of steady-state concentration profiles in the human eye (247) from a hypothetical device that releases drug toward the front of the eye, for a low-molecular-weight drug that is efficiently eliminated through the retina. Solid contours represent changes of 1 log unit with the eye under zero pressure. Dashed contours show the influence of the normotensive 5 mmHg intraocular pressure difference between the ocular interior and the episclera.

subconjunctival injection of 6-mercatopurine, mean peak concentrations in aqueous and vitreous were 15 and 10 times those following intravenous administration, while serum levels were about half (270). In another example, rabbits administered 14C-5-fluoruracil either subconjunctivally or intravenously exhibited similar peak levels of parent in the serum and urine for the two routes; however, subconjunctival injection resulted in peak aqueous concentrations of 125 and 380 times that after intravenous injection (271).

The mechanism for ocular penetration following subconjunctival administration has been studied by Maurice and Mishima, who identify direct penetration into deeper tissues as the main absorption pathway (18), with the prerequisite condition that the sclera be saturated with drug. The consequential diffusion can occur by various routes: (i) laterally into corneal stroma and across the endothelium, (lï) across trabecular meshwork, (ill) through the iris stroma and across its anterior surface, (iv) into the ciliary body stroma and into newly generated aqueous humor, and (v) into the vitreous body via the pars plana and across its anterior hyaloid membrane (18). In addition to these pathways, direct transcorneal absorption can result from a mechanism dependent on the dose volume in which excess volume injected is squeezed out from the injection site with subsequent spillage onto the cornea. For example, Conrad and Robinson demonstrated that, at high injection volumes (>200 |iL), the primary mechanism for uptake into the aqueous was reflux of the drug solution from the injection site followed by corneal absorption (272). At lower volumes, the mechanism involved reflux and transconjunctival penetration, permeation of the globe, and systemic absorption followed by redistribution.

Periocular injection (sub-Tenon's and retrobulbar) More posterior, sub-Tenon's or juxtascleral, injection involves periocular delivery of drug, usually forming a depot, between the sub-Tenon's capsule and sclera or episclera. This route conveniently places drug in very close proximity to, or in direct contact with, the sclera. Given that the sclera is quite permeable to a wide range of molecular weight compounds, most drugs easily diffuse through the sclera to underlying tissues (198,273). However, the diffusion of drug from the dose site can be highly localized, so the preferred location of dose is directly external to the target, for example, the macula. Freeman et al. injected corticosteroid sub-Tenon's and used echography to show drug within the sub-Tenon's space over the macula in 11 of 24 cases (274). They attributed the lack of therapeutic response to inaccurate placement relative to target.

Retrobulbar (or peribulbar) injection administers drug around the eyeball, usually posteriorly, but not necessarily juxtasclerally. With injection of a depot, drug delivery can be sustained, allowing for relatively infrequent injections. Hyndiuk and Reagan have demonstrated the penetration and persistence of retrobulbar depot corticosteroid in monkey ocular tissues (275). Concentrations of drug were high in posterior uvea and ultimately sustained at lower concentrations. Steroid concentrated in the optic nerve after retrobulbar but not after systemic administration. No drug was detected in other ocular tissues, with the exception of lens and vitreous, after two and nine days. Weijten et al. studied the penetration of dexamethasone into the human vitreous and its systemic uptake following peribulbar injection (276). Mean levels in the vitreous peaked at 13 ng/mL at 6 to 7 hours postdose, and maximal serum level was 60 ng/mL at 20 to 30 minutes postdose.

Systemic administration Systemic administration is generally not preferred for treatment of posterior-segment eye diseases because most drugs poorly penetrate the blood-retinal barrier, including both the inner (microvessel endothelial cells) and outer (RPE) layers (277). As a result, large doses must be administered orally or intravenously, thus increasing the probability of systemic side effects. On the other hand, local ocular delivery typically provides direct access to the site of action and, in most cases, substantially reduces systemic exposure and toxicity. However, for drug delivery to the posterior segment or vitreous body, systemic administration could be the best choice depending on the drug's ability to penetrate the blood-retinal barrier or blood-vitreous barrier and its systemic toxicity profile. For example, in a study by Ueno et al., concentrations of the anticancer drug BCNU (also known as carmustine) were measured in aqueous and vitreous of rabbits following intravenous, subconjunctival, and topical ocular administration (278). Distribution was dependent on dose route in that topical, followed by subconjunctival, was best for distribution into the iris, while intravenous was best for distribution into the choroid-retina. In another example, Liu et al. demonstrated that rifampin penetrated vitreous humor after an intravenous single dose (279).

Disruption of the blood-vitreous or blood-retinal barrier can augment ocular absorption following systemic administration. For example, in a study by Elliot et al., following intravenous injection of ganciclovir with and without the bradikynin analog RMP-7, a compound known to increase the permeability of the blood-brain barrier, RMP-7 enhanced retinal uptake through the blood-retinal barrier (280). In another example, Wilson et al. demonstrated increased intravitreal penetration of carboplatin in rabbit eyes treated with triple or single freeze-thaw cryotherapy at one or two locations, one day before intravenous carboplatin with or without cyclosporine (281). In general, however, if systemic exposure can be prevented, this is to be preferred.

Topical ocular distribution to the posterior segment Historically, ophthalmologist and vision scientists have accepted the dogma that drugs applied topically to the eye do not reach therapeutic levels in the posterior segment tissues, except perhaps by way of absorption from the precorneal area into the systemic circulation and redistribution to the posterior segment tissues (198). The local distribution pathway was considered therapeutically irrelevant. There are a growing number of studies, however, challenging this dogma. The history and more recent evidence of topical delivery to the posterior segment are summarized elsewhere (277,282).

Local distribution of an effectively administered topical ocular drug is exemplified in a study by Hollo et al., who estimated the contributions of local ocular versus systemic delivery to posterior-segment concentrations of betaxolol at steady state following multiple topical dosing of Betoptic S in monkeys and humans (283). Significant levels of betaxolol were found in the retina and optic nerve head. A comparison of concentrations of dosed versus nondosed ocular tissue in monkeys revealed that most of the drug in the posterior segment was from local delivery (absorption), with some contribution from the systemic plasma. High concentrations in the iris-ciliary body, choroid, and sclera suggested the presence of a depot that presumably facilitated transfer to the retina and optic nerve head. Further evidence of local distribution after topical administration was provided by Chien et al., who evaluated the ocular distribution of brimonidine in albino and pigmented rabbits following a single topical ocular dose of 14C-labeled drug (284). The results indicated that drug was retained in choroid-retina and optic nerve head. Levels in the nondosed contralateral eyes were much lower than those in the treated eyes for both albino and pigmented rabbits, suggesting that the majority (>99%) of the intraocularly absorbed drug was due to local topical application and not to redistribution from plasma.

The mechanism by which drugs may be locally delivered to the posterior segment from the precorneal area is not fully understood, but the evidence seems to indicate a noncorneal route, possibly involving conjunctival/scleral absorption followed by distribution to choroid, vitreous, and retina. Hughes et al. have proposed four routes of entry and distribution: (i) diffusion into the posterior chamber via the iris root and subsequently into the posterior tissues; (ii) entry via the pars plana, followed by distribution posteriorly; (ill) lateral diffusion along the sclera with subsequent penetration of Bruch's membrane and the RPE; and (iv) absorption into the systemic circulation via the conjunctival blood vessels or via the nasolacrimal duct, followed by redistribution to the retina (277). This evidence suggests that topically applied drugs that are effective in reaching the retina achieve this target not by passing through the vitreous or anterior chamber but by a more efficient route through the conjunctiva and sclera.

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