section 4: Drugs and Mechanisms in Retinal Diseases

Nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of retinal diseases

Eduardo Büchele Rodrigues, MD, Michel Eid Farah, MD, Juliana Mantovani Bottós, MD, and Fabio Bom Aggio, MD

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KEY FEATURES

Retinal pharmacotherapy has evolved vastly in recent years. Retinal diseases such as choroidal neovascularization (CNV) or macular edema (ME) can be currently managed with local or systemic application of drugs such as corticosteroids or monoclonal antibodies. However, such agents have major side-effects, including glaucoma, cataract, and inflammation. As a result, nonsteroidal anti-inflammatory drugs (NSAIDs) have arisen as great alternative pharmacologic agents. Nevanac, diclofenac, ketorolac and bromfenac are some notable NSAID candidates which should be investigated intravitreally or topically for retinal pharmacotherapy (Figure 29.1).

INTRODUCTION AND HISTORY

In ophthalmology, NSAIDs were initially used for the prevention of intraoperative miosis. However, they were later found to have a modulating effect on ocular inflammation and pain through the prevention of prostaglandin (PG) synthesis via cyclooxygenase (COX) inhibition. More importantly, NSAIDs have also been found to be effective in the prevention and treatment of cystoid macular edema (CME) secondary to cataract surgery.1–3

The use of NSAIDs for various vitreoretinal conditions has become a reasonable therapeutic approach in recent years. For retinal pharmacotherapy, the ideal drug would penetrate target intraocular tissues at therapeutic levels, thereby reaching high concentrations in both the uveal tract and posterior segment. In this way, desired effects such as pain reduction as well as the prevention and treatment of anteriorand posterior-segment inflammation or edema could be achieved. COX inhibitors are potent anti-inflammatory agents that have shown a quite safe profile when applied to the ocular surface. Some COX inhibitors that have been proposed for retinal diseases in the recent past include nepafenac, diclofenac, and ketorolac.3

PHARMACOLOGY, DRUG MECHANISM, AND EFFECTS

DICLOFENAC

Diclofenac sodium (Voltaren Ophthalmic, Novartis), 0.1% ophthalmic solution, is a sterile topical NSAID product for ophthalmic use. Diclofenac sodium is designated chemically as 2-[(2,6-ichlorophenyl) amino] benzeneacetic acid, monosodium salt, with an empirical formula of C14H10C12NO2Na, molecular weight of 318, and osmolarity of 300 mOsmol/ml. Diclofenac sodium is a faintly yellow-white to lightbeige, slightly hygroscopic crystalline powder. It is freely soluble in methanol and sparingly soluble in water. An oily solution has been formulated in an attempt to overcome the poor water solubility of diclofenac. Results from a bioavailability study established that plasma

levels of diclofenac following ocular instillation of two drops of Voltaren Ophthalmic to each eye were below the limit of detection (10 ng/ml) over a 4-hour period. This study suggests that limited, if any, systemic absorption occurs with Voltaren Ophthalmic.1,3,4 Apart from the commercially available conventional dosage form, various other delivery systems such as novel polydisperse carrier solution (Sophisen), ophthalmic gels, ocular inserts, and liposomes of diclofenac have been evaluated. Polydisperse carrier solutions of diclofenac were reported to provide better tolerance and sustained release of diclofenac. In addition, precorneal retention of diclofenac sodium has been reported to be increased by the use of liposomes.1,2

KETOROLAC

Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of NSAIDs for ophthalmic use as 0.5% solution (Acular, Allergan, USA). The chemical name for ketorolac is benzoyl-2,3-dihydro-1H- pyrrolizine-1-carboxylic acid, and its chemical formula is C19H24N2O6. In its commercial formula, ketorolac tromethamine 0.4% contains a preservative, 0.006% benzalkonium chloride, and it is supplied as a sterile isotonic solution with a pH of approximately 7.4. Among all the formulations, ketorolac tromethamine ophthalmic solution containing benzalkonium chloride and ethylenediamine tetraacetic acid (EDTA) provided more extensive corneal penetration. The osmolarity of Acular ophthalmic solution is approximately 290 mOsmol/kg.

It has been observed that unbuffered ketorolac tromethamine drops of pH 6.5–8.5 provided enhanced chemical stability. Ketorolac tromethamine may exist in three crystal forms, all of which are equally soluble in water. Acular is commercially available as a tromethamine salt and has higher water solubility compared to ketorolac. Acular ophthalmic solution is a racemic mixture of R-(+) and S-(–)- ketorolac tromethamine. As with other NSAIDs, the mechanism of the drug is associated with the chiral S form, as conversion of the R enantiomer into the S enantiomer has been shown to occur in its metabolism. Thus, the chemical form and physical state of the drug could affect ocular permeation.2,5

Investigations on the in vitro corneal penetration of ketorolac revealed that reducing the pH of the formulation increased the corneal penetration of ketorolac. Both ketorolac free acid and ketorolac tromethamine have also been formulated as ointment dosage forms. In vivo comparison of the aqueous, oil, and ointment formulations of ketorolac for ocular availability in rabbits revealed that the ketorolac drops formulated in oil provided prolonged precorneal residence and sustained effect. The mechanism of action for ketorolac’s anti-inflam- matory, antipyretic and analgesic effects refers to the specific biochemical interaction through inhibition of PG synthesis by competitive blocking of the enzyme, and, like most NSAIDs, it is a nonselective COX inhibitor.6,7

NEVANAC

Nepafenac (Nevanac, Alcon Labs, USA) is a prodrug with low inherent COX-inhibiting activity. The active NSAID compound of nepafenac is

O

Figure 29.1  Physicochemical characteristics of various nonsteroidal anti-inflammatory drugs used in ocular and retinal pharmacotherapy. The two columns to the right of the chemical structures show the pKa and molecular weight of the drugs.

called amfenac (2-amino-3-benzoylbenzeneacetic acid) which is an NSAID with an arylacetic acid structure exhibiting potent antipyretic and analgesic properties (Figure 29.2). Nepafenac is designated chemically as 2-amino-3-benzoylbenzeneacetamide with an empirical formula of C15H14N2O2 and molecular weight of 254.28 g/mol. Nepafenac ophthalmic suspension 0.1% was recently made available for ophthalmic use and supplied as a sterile drug with a pH of approximately 7.4 and an osmolality of 305 mOsmol/kg.8 As a prodrug, nepafenac is a less active form of the drug, which is converted to the more active form, amfenac, after metabolic conversion through intraocular enzymatic hydrolysis. Nepafenac is a member of the new class of NSAID prodrugs for ophthalmic use, providing a novel drug delivery mechanism. The analgesic and anti-inflammatory effect of nepafenac is the result of its fast penetration through the cornea in addition to conversion to amfenac. The superior corneal permeability of nepafenac is likely due to its molecular structure; it is an uncharged molecule whereas the other NSAIDs have acidic structures.9

The conversion of nepafenac to amfenac occurs predominantly in the intraocular vascular tissues, especially in the retina and choroid. The nepafenac conversion rates are higher in more posterior sites within the eye because of the higher hydrolase activity in these tissues. It is twice as high in the ciliary body when compared with that in the cornea and 20 times higher in the retina and choroid than in the cornea.

Figure 29.2  Nepafenac is converted to a potent cyclooxygenase inhibitor, amfenac, by intraocular hydrolases.

While nepafenac exhibits some COX inhibition, the activated form, amfenac, is a potent inhibitor of both COX-1 and COX-2 activities. The analgesic action of NSAIDs has also been attributed both to the reduction of PG synthesis and to a direct effect on the excitability of ocular nociceptor sensory nerve terminals by nepafenac. The rapid onset of nepafenac analgesic action is probably due to an inherent analgesic activity and a rapid saturation of the corneal epithelial layer, highly innervated by nociceptors.

Corneal epithelial concentrations of nepafenac may be initially sufficient to attenuate corneal nociceptor PG formation without invoking an immediate conversion to amfenac. Nepafenac has been shown to inhibit PG synthesis in both the anterior and posterior portions of the eye following a single topical ocular application in animal models.2,9 Following a single dose of Nevanac in 25 cataract surgery patients, aqueous humor concentrations were measured at 15–60 minutes postdose. The maximum mean aqueous humor concentrations were observed at the 1-hour time point (nepafenac, 177 ng/ml; amfenac, 44.8 ng/ml), indicating rapid corneal penetration. Following a three- times-daily dosing of nepafenac eye drops in both eyes, low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects 2 and 3 hours postdose. The mean steadystate plasma concentration (Cmax) for nepafenac and for amfenac were 0.310 ± 0.104 and 0.422 ± 0.121 ng/ml respectively following ocular administration.

BROMFENAC

Bromfenac ophthalmic solution 0.09% (Xibrom, Senju Pharmaceuticals, Japan) is a sterile topical NSAID for ophthalmic use. Each milliliter of Xibrom contains 1.035 mg bromfenac sodium (equivalent to 0.9 mg bromfenac free acid). Bromfenac sodium is designated chemically as sodium 2-amino-3-(4-bromobenzoyl) phenylacetate sesquihydrate, with an empirical formula of C15H11BrNNaO3 and molecular weight of 383.17. The osmolality of Xibrom ophthalmic solution is approximately 300 mOsmol/kg. The commercially available formulation is buffered to pH 8.3 and contains polysorbate 80 as solubilizer and benzalkonium chloride (0.005%) as preservative.10 It shows good ocular penetration, and significant amounts are also absorbed systemically after topical administration.

The introduction of bromine in bromfenac makes it more lipophilic, facilitating corneal penetration, increased duration of action, and enhanced COX-2 inhibitory activity. Bromfenac has been found to be 3.7, 6.5, and 18 times more potent in inhibiting COX-2 than diclofenac, amfenac, and ketorolac, respectively. Aqueous drops of the sodium salt (containing an equivalent of 0.09% wt/vol bromfenac) have been used in the management of postoperative ocular inflammation and pain in patients after undergoing cataract extraction. The plasma concentration of bromfenac following ocular administration of 0.09% Xibrom in humans has not been thoroughly studied so far. Based on the maximum proposed dose of one drop to each eye (0.09 mg) and pharmacokinetics data from other routes of administration, the systemic concentration of bromfenac is estimated to be below the limit of detection (50 ng/ml).2,10

Diseases Retinal in Mechanisms and Drugs • 4 section

Diseases Retinal of Treatment the in (NSAIDs) Drugs Inflammatory-Anti chapNonsteroidal• 29

DRUG USE IN OCULAR AND

RETINAL DISEASES

DICLOFENAC

Diclofenac sodium 0.1% solution has been shown to be effective as a prophylactic treatment against the development of CME after cataract surgery, and it has also been approved for inflammation after cataract surgery. Effects of topically applied NSAIDs in eyes undergoing cataract surgery have been demonstrated in many randomized prospective controlled clinical studies. Diclofenac 0.1% seems to be one of the most effective NSAIDs, where the decrease in inflammatory response has been over 30% in eyes treated with diclofenac sodium compared to other NSAID ophthalmic solutions.1,11 Moreover, the inflammatory response can be quite enhanced with a combination of diclofenac 0.1% and dexamethasone 0.1%. In addition, diclofenac may be applied topically in the eye for the management of pain in corneal epithelial defects following surgery or accidental trauma, treatment of postoperative ocular inflammations, chronic noninfectious inflammations, prevention of intraoperative miosis during cataract surgery, and for symptomatic relief of seasonal allergic conjunctivitis. Some studies could also demonstrate positive effects in managing symptoms of acute allergic conjunctivitis with topical diclofenac sodium 0.1% and treating contact lens-associated giant papillary conjunctivitis or venereal conjunctivitis with suprofen. Diclofenac 0.1% is also approved by the Food and Drug Administration (FDA) to reduce photophobia and pain after refractive surgery. Recently topical diclofenac has been proposed as useful adjuvant therapy to photodynamic therapy in the treatment of CNV.12

KETOROLAC

Pharmacodynamic evaluation of aqueous, oily, and ointment formulations of ketorolac in PGE2-induced ocular inflammation in animals established the efficacy of ketorolac formulations in inhibiting many inflammatory cytokines. Ketorolac 0.5% is FDA-approved to reduce photophobia and pain after refractive surgery. Kaiser et al. compared corneal healing time after contact lens-unrelated traumatic corneal abrasion (less than 10 mm in diameter) in patients with patching and patients who received ketorolac 0.5% without patching.13 In this study, ketorolac tromethamine 0.5% ophthalmic solution promoted enhanced comfort without clinical adverse effects when used as adjunctive therapy in the treatment of noninfected, noncontact lens-related, traumatic corneal abrasions.

Ketorolac has been also applied topically in the management of seasonal allergic conjunctivitis. Of the topical NSAIDs, ketorolac tromethamine 0.5% ophthalmic solution has been shown to be effective in the treatment of established chronic aphakic and pseudophakic CME. Subsequent studies of the prophylactic use of topical NSAIDs including ketorolac demonstrated a reduction in angiographic CME, but a statistically significant reduction has been difficult to establish. A systematic review of the literature for randomized controlled trials that evaluated the effects of NSAIDs in the treatment of CME following cataract surgery was done according to the Cochrane Collaboration methodology; treatment with topical 0.5% ketorolac for chronic CME was found to be effective in two trials.14

NEPAFENAC

The effectiveness of nepafenac was initially examined in experimental studies using animal models. Nepafenac’s inhibitory efficacy and longer duration of action were demonstrated by assessing protein and PGE2 accumulation in aqueous humor in a trauma-induced rabbit model of acute ocular inflammation. The preclinical pharmacodynamic profile exhibited by nepafenac indicates the potential to suppress PG-mediated inflammation in both anterior-segment tissues and retinal tissue following topical ocular administration. In rabbit tissue, the greater corneal permeability of nepafenac was demonstrated by a per-

meability coefficient that was approximately 4 times greater than that of diclofenac, 19 times greater than that of bromfenac, and 28 times greater than that of ketorolac.15 Nepafenac has also exhibited superior pharmacodynamic properties in the posterior segment following topical ocular dosing, suggesting a unique therapeutic potential for a variety of conditions associated with retinal edema, subretinal fluid, or exudation. Topical nepafenac reaches the retina of rats in sufficient concentrations to inhibit multiple biochemical and morphologic abnormalities of the early stages of diabetic retinopathy in animals. Topical nepafenac also seems to inhibit CNV and ischemia-induced retinal neovascularization in mice, by decreasing the production of vascular endothelial growth factor.16 Nepafenac 0.1% also prevented the development of induced panretinal edema following topical ocular application in the rabbit.

Nepafenac has been shown to be well tolerated and effective in the prevention and treatment of inflammation and ocular pain associated with cataract surgery and pseudophakic CME (Figure 29.3). The preoperative administration of topical NSAIDs prevents inflammation by inhibiting the COX pathway before surgical trauma induces the activation of PG production. Used after surgery, NSAIDs inhibit the continued PG formation that persists for days after cataract surgery.2 In August 2005, the US FDA approved nepafenac for the treatment of pain and inflammation after cataract surgery. The approved dosing regimen is one drop 3 times daily, starting 1 day before surgery and continuing for 14 days after surgery. Five unpublished clinical trials supported the efficacy and safety of nepafenac ophthalmic suspension for its approval.17,18 The cataract surgery studies consisted of one pivotal trial, one efficacy and safety study, two dose–response studies, and one trial comparing nepafenac with diclofenac regarding safety and tolerability. A placebo-controlled dose study (C-02-53) was conducted on 212 patients to determine the efficacy of QD, BID, and TID nepafenac 0.1%. Both QD and BID dosing produced significantly less anterior-segment inflammation and less ocular pain than placebo. In a randomized, placebo-controlled trial of 476 patients undergoing cataract surgery (C-03-32), nepafenac 0.1% was statistically superior to placebo in painfree rate and reducing anterior-segment inflammation. The two dose– response studies C-95-93 and C-97-30 compared nepafenac suspension concentrations ranging from 0.003% to 0.3%. All the concentrations were shown to be efficacious in the treatment of inflammation due to cataract surgery.

In more recent years, numerous studies of case series have been conducted in humans to analyze the safety and efficacy of nepafenac and to understand better the ability of topical NSAIDs to reach various tissues in the eye. Nepafenac concentrations in the aqueous humor peaked at the first time point (30 minutes) and declined steadily thereafter, in contrast to the low levels of amfenac. These observations are consistent with the hypothesis that nepafenac serves as a source for continued amfenac production; the early rise, then decline in prodrug concentration and concomitant increase in amfenac concentration can be explained by the conversion of the former drug into the latter. Recent reports indicated that nepafenac may be useful in the therapy of other forms of ME (Figure 29.4).2

BROMFENAC

Bromfenac (Xibrom, ISTA Pharmaceuticals, Irvine, USA; Bronuck, Senju Pharmaceutical, Osaka, Japan) is indicated for the treatment of postoperative inflammation and the reduction of ocular pain in patients after undergoing cataract extraction. For this task, one drop of Xibrom may be applied to the affected eye twice daily beginning 24 hours after cataract surgery and continuing for the first 2 weeks of the postoperative period. The clinical safety and efficacy of bromfenac have been extensively studied in diverse comparative investigations, including the treatment of external or anterior ocular inflammatory diseases, allergic conjunctivitis, scleritis, and postoperative inflammation.10 The results of two phase III multicenter, randomized double-masked placebo-controlled clinical trials showed that bromfenac ophthalmic solution 0.09% was effective in the rapid resolution of ocular pain after cataract surgery, and there was a statistically significant difference

Figure 29.3  Optical coherence tomography demonstrates improvement of cystoid macular edema after the use of nepafenac TID for 14 days.

Figure 29.4  Optical coherence tomography showing the use and effect of nepafenac as adjuvant therapy in a case of pigment epithelium detachment associated with age-related macular degeneration. Anatomical improvement was observed after 30 days using nepafenac TID.

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