Vitrectomy and Injections Intravitreal Retina: and Eye the to Delivery Drug for• 10Routeschapter

COMBINATION OF SURGICAL WITH

PHARMACOLOGICAL THERAPIES34–44

A pars plana vitrectomy combined with pre-, intra-, and postoperative application of drugs has been recommended by numerous authors. The Endophthalmitis Vitrectomy Study demonstrated that early antibiotic drug application may limit the progression of moderate infection, while severe endophthalmitis cases require an early vitrectomy combined with intraoperative application of antibiotics.3

PREOPERATIVE DRUG APPLICATIONS

The concept of a planned consecutive intravitreal drug application prior to vitrectomy has been proposed in eyes with severe vitreoretinal adhesions, infections, inflammation, or bleeding, e.g., epiretinal membrane, proliferative vitreoretinopathy, diabetic vitreoretinopathy,33 retinopathy of prematurity,35 endophthalmitis, uveitis, or subretinal hemorrhage.

Enzymatic or pharmacologic vitrectomy may induce a cleavage of the posterior hyaloid from the adjacent retinal surface. Dispase, collagenase, hyaluronidase, rtPA36,38; RDG peptides,37 plasmin,34,35 or microplasmin have been recommended to induce a release of the vitreous from the retina, thus inducing an easier, faster, or less traumatic detachment of the posterior hyaloid. Resolution of a diffuse vitreal hemorrhage may be induced by a liquefaction of the vitreous gel. Highly purified bovine hyaluronidase (Vitrase) has been approved as a complementary approach for the management of vitreous hemorrhage.

Liquefaction of subretinal hemorrhages may be achieved by intravitreal injection of rtPA. Additional SF6 gas injection can assist the massage of the blood from the subfoveal area towards an inferior location.38 We proposed a triple injection with rtPA, gas, and anti-VEGF injection in order to occlude the subretinal choroid neovascularization as the primary cause of the bleeding. If the subretinal hemorrhage remains under the fovea or the size of the subretinal hemorrhage is too large, vitrectomy and subretinal lavage of the liquefied blood are recommended. The triple intravitreal injection may increase the intraocular pressure, requiring paracentesis.39 Koch et al.45 proposed a minivitrectomy to reduce the volume prior to the drug application. These authors designed a combined 23-gauge vitreous cutter and injection line, Intrector, in order to reduce the vitreous volume, inducing a posterior vitreous detachment and better penetration of the drug through the vitreous cavity and finally consecutive drug application through a single sclerotomy. Initial pilot studies revealed no severe complications using this novel technique. The usefulness of this concept needs additional assessments in further studies.

Eyes with severe nonproliferative diabetic retinopathy or secondary glaucoma (rubeosis iridis) may benefit from intravitreal injected VEGF inhibitors or steroids. Most surgeons apply TA or bevacizumab 3–10 days prior to surgery in order to seal the retinal vessels and reduce the risk of intraoperative bleeding.40–44,46 However, the fast occlusion of the proliferative vessels can induce traction on the vitreous and retinal surface. Eyes with severe proliferative diabetic retinopathy may therefore develop severe tractional retinal detachments when bevacizumab is applied alone, without subsequent removal of the vitreous gel by vitrectomy.47 A vitrectomy should be assigned only a few days later, avoiding this devastating complication.

INTRAOPERATIVE DRUG APPLICATIONS

Consecutive drug applications during vitreoretinal surgery have become a frequent maneuver. The selective staining of cellular components in epiretinal membrane or extracellular matrix components on the retinal surface such as the inner limiting membrane (ILM) may be visualized during vitrectomy by a variety of vital dyes (chromovitrectomy). Numerous vital dyes, including indocyanine green, tryphan blue, brilliant blue, patent blue, and triamcinolone, have been proposed to stain the vitreous, epiretinal membranes, or ILM during chromovitrectomy. A better visualization of these semitransparent structures can

help to visualize the fine semitransparent structure during surgery, limiting the damage of delicate adjacent structures.47

Retinal detachments are frequently treated by removal of the vitreous, drainage of subretinal fluid, and intravitreal gas instillation. Intravitreal gas may assist a permanent reattachment of the retina, sealing the retinal tear during the early postoperative period. The persistence of the gas bubble in the vitreous cavity depends on the type of applied gas. While SF6 has persisted with different durations in the vitreous cavity, recently, Jackson48 applied vital dyes into the subretinal space during pars plana vitrectomy in eyes with bullous rhegmatogenous retinal detachments, in order to visualize the retinal break by dye leakage from the subretinal space into the vitreous cavity.

POSTOPERATIVE DRUG APPLICATIONS

Intravitreal drug applications at the end of surgery or early after surgery may support the healing process. Avitrectomy can release the tractional components in diabetic macular edema; however, the edema may persist due to damage of the BRB. Severe uveitis is also frequently associated with a severe breakdown of the BRB. Both indications frequently demonstrate a faster healing process as well as better functional and anatomical improvement after surgery when an intravitreal triamcinolone injection is applied as an adjunct at the end of surgery. The TA crystals may settle on the retinal surface in the inferior quadrant without damaging the retinal surface.40,41 Unintended application of TA crystals has been observed even in a macular hole early after vitrectomy; however the hole closed without complication and the visual acuity improved to 20/80, demonstrating safety even in this delicate location.

SUMMARY AND KEY POINTS

The rationale for intravitreal drug application is an immediate and increased therapeutic delivery to the targeted tissue. Intravitreal drug application is a safe and effective procedure. Possible side-effects, e.g., elevated intraocular pressure, cataract formation, and endophthalmitis, are limited. The pharmacokinetics depends on the status of the vitreous as well as the structure of the drug. Combined surgical and pharmacological approaches have become an efficient approach to deliver drugs in therapeutic levels to the posterior segment.

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delivery drug retinal for routes and models Animal • 2 section

INTRODUCTION

Targeted drug delivery to the retina is an active area of research, presently under intense investigation. Multiple routes and various methods, devices, and formulations of both pharmaceutical agents and biologics are being investigated. The goal of this research is to provide local drug therapy to the retina, a tissue that is very small, estimated to be 200 m thick.1 Gaining access for drug delivery to the retina, given certain anatomical constraints, is challenging. However, if a method for local delivery is achieved for a given condition, therapy to such a small tissue will require extremely small doses relative to the dose that would be required for systemic therapy. Local therapy will minimize systemic drug levels and limit potential systemic toxicity.

Testing local tissue levels with various drug delivery devices and methodologies in humans is not usually possible. The most representative pharmacokinetic human data is obtained by collecting either aqueous or vitreous samples, under strict institutional review board approval, and done in conjunction with a predetermined therapeutic intervention. Computer modeling systems that predict tissue levels in the human eye are also under investigation.2,3 However, with limited data on tissue barriers, choroidal blood flow, aqueous diffusion kinetics, orbital blood flow, vitreous kinetics and liquefaction, the reliability of determining tissue levels in humans is limited. As more accurate data is acquired, better parameters may be utilized for more sophisticated modeling.

The best possible method to understand the pharmacokinetics of drug delivery to the retina is through carefully designed studies using appropriate animal models. Even using the best possible model, human disease states, such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP) may alter pharmacokinetics in unpredictable ways. Using the most appropriate animal model to study a given therapeutic agent is important. For example, using a rabbit model to study the pharmacokinetics of an intravitreal injection used to treat endophthalmitis is a reasonable approach. On the other hand, using a mouse or rat model to determine topical delivery for a chronic retinal disorder is less optimal. While such a model system may provide an answer to therapeutic efficacy, the pharmacokinetics are much too disparate from the human condition to apply directly to the clinical arena. Simple principles of pharmacokinetics, such as diffusion, variations in diffusional barriers, aqueous kinetics, vitreous liquefaction, and other factors become critical in predicting therapeutic responses to local delivery.

Recent advances in pharmacotherapeutic options for treating disorders of the posterior pole increase the need for effective methods of delivery. Examples of agents that may be useful in treating retinal and optic nerve disorders include anti-vascular endothelial growth factor (anti-VEGF) agents,4–7 neuroprotectants,8–10 antioxidants,11 corticoste- roids,12–14 and other specific biologic agents (e.g., ciliary neurotrophic factor15–17).

anterior-segment structures, such as the cornea, conjunctiva, anterior chamber, iris, and ciliary body. However, diffusional barriers limit the ability of topical agents to achieve therapeutic levels to the posterior pole, optic nerve, and retina. The primary barriers for topical drug delivery to the retina include the corneal and conjunctival epithelium,18 diffusion through the cornea and scleral stroma,18,19 corneal endothelial barriers,20 and variations in diffusion from aqueous flow, choroidal blood flow,21 conjunctival blood flow, and liquefaction of the vitreous. Key variables, such as scleral thickness and surface area, have been documented in humans as well as large-animal models to help in translational studies of pharmacokinetics with direct correlation to the human condition.19,22,23 Effects from the lens, the internal limiting membrane of the retina, and the blood–retinal barrier also play an important role in pharmacokinetics. Some of the most important work in the investigation of pharmacokinetics of drug delivery was derived from physiologists studying aqueous pathways. For example, pioneering ocular physiologists such as Irving Fatt24 and Anders Bill,25 in their studies of uveoscleral outflow facility, originated important principles of transscleral drug delivery (TSDD) that we use today. Essentially TSDD physiology follows pathways identified in uveoscleral outflow studies, in a reverse direction.26,27

KEY CONCEPTS

Development and design of drug delivery systems and methodologies need to fit the intended disease. For example, an acute disease process with a short duration is best treated with a pulsed-dose delivery system. Endophthalmitis is an acute disease, requiring a high dose of antibiotic that can be administered with a single intravitreal injection of a therapeutic antibiotic. On the other hand, treating a chronic disease such as glaucoma or atrophic (dry) AMD with a direct intravitreal injection may not be practical, especially given the limited duration of an injection and the need for repeat injections. Exudative (wet) AMD is a subacute phase of a chronic disease and has been treated very effectively with repeated intravitreal injections. However, multiple injections have limitations, including patient tolerability, inconvenience, safety concerns, peak-trough pharmacokinetics, as well as expense. Therefore, treatment of chronic disease or even prolonged subacute disease may be best addressed with a long-acting sustained delivery system or improved drug formulation.

Some concepts that relate to the profile of an ideal delivery system include: (1) sustained and predictable delivery; (2) safety of the device or methodology for the ocular tissues; (3) rechargeable, readily replaceable or regenerative capacity; (4) removable; and (5) compatible with normal visual function. Many systems optimize certain aspects of the ideal system. Matching the delivery system with the underlying disease process is important.

Topical medications have been available for many years, and represent the mainstay of pharmacotherapy to the eye (Figure 11.1), particularly

Various animal model systems for studying drug delivery to the retina have been studied, each with its own advantages and disadvantages.