Expert Opinion on Drug Metabolism & Toxicology
ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis Xiao Chloe Wan & Vesselin Dimov To cite this article: Xiao Chloe Wan & Vesselin Dimov (2014) Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis, Expert Opinion on Drug Metabolism & Toxicology, 10:4, 543-549, DOI: 10.1517/17425255.2014.884070 To link to this article: https://doi.org/10.1517/17425255.2014.884070
Published online: 03 Feb 2014.
Submit your article to this journal
Article views: 188
View related articles
View Crossmark data
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iemt20
Review
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis 1.
Introduction
2.
Pharmacodynamics of topical calcineurin inhibitors
3.
Pharmacokinetics
4.
Safety profile
5.
Clinical efficacy
6.
Conclusion
7.
Expert opinion
Xiao Chloe Wan & Vesselin Dimov† †
University of Chicago, Department of Pediatrics and Medicine, Section of Allergy, Asthma and Immunology, Chicago, IL, USA
Introduction: Topical calcineurin (Cn) inhibitors delivered via ophthalmic drop is emerging as a potential treatment for severe, immune-mediated forms of allergic conjunctivitis, such as vernal keratoconjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis. Areas covered: This article is based on a comprehensive literature search, with information taken from meta-analyses, systematic reviews, treatment guidelines and clinical studies in children and adults. The articles that have been selected evaluate the use of topical Cn inhibitors and their role in the treatment of allergic conjunctivitis. Expert opinion: Ophthalmic topical Cn inhibitors have been shown to be safe for short-term use, with minimal systemic absorption and toxicity. For patients with severe, refractory forms of allergic conjunctivitis, topical Cn inhibitors offer a promising treatment option and an alternative to steroidal therapies. The safety profile and efficacy data for topical cyclosporine are more robust compared to that of tacrolimus and pimecrolimus, although larger trials will be needed for all three agents. With more randomized controlled trials involving larger sample sizes and long-term follow-up to establish both efficacy and safety, ophthalmic Cn inhibitors offer exciting treatment possibilities for the prevention of morbidity associated with refractory allergic conjunctivitis. Keywords: allergic conjunctivitis, cyclosporine, tacrolimus, topical calcineurin inhibitors Expert Opin. Drug Metab. Toxicol. (2014) 10(4):543-549
1.
Introduction
Approximately one-third of the world’s population is affected by some form of allergic disease, and of those, 40 -- 80% have ocular allergic symptoms [1]. Allergic conjunctivitis can be divided into five sub-categories: seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC) [2]. SAC and PAC are caused by IgE reaction to environmental airborne allergens that specifically activate mast cell to release histamine, thus triggering symptoms such as eye irritation, itchiness, dryness and conjunctival injection. SAC and PAC are considered milder from the symptomatic perspective, and can typically be controlled with mast cell stabilizers and antihistamine agents. VKC, AKC and GPC are rarer forms of allergic conjunctivitis, and are typically lymphocyte cell-mediated in addition to IgE-mediated, with more severe symptoms and significant long-term consequences, often requiring topical steroids for control. However, prolonged use of topical steroids are not without its side effects, including elevated intraocular pressure, development of cataracts and increased susceptibility to microbial infection that can be vision threatening [3]. Thus, many of the topical calcineurin (Cn) inhibitors are used to treat VKC, AKC and GPC, with the goals of better symptom control and tapering of topical steroids. 10.1517/17425255.2014.884070 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
543
X. C. Wan & V. Dimov
Article highlights. .
.
.
.
.
Ophthalmic topical calcineurin (Cn) inhibitors such as cyclosporine and tacrolimus have been shown to be safe for short-term use with little systemic absorption and toxicity. Most common side-effects include burning and discomfort upon distillation and are generally well tolerated, with few incidences of possible ocular surface viral or bacterial infection. Small clinic studies suggest that ophthalmic cyclosporine drops are more effective compared to placebo and may be equally efficacious to topical steroids at relieving symptoms of severe allergic conjunctivitis. Ophthalmic tacrolimus drops are less readily available, but may also be effective at relieving symptoms of severe allergic conjunctivitis. Larger, randomized controlled trials will be needed to better examine the long-term safety profile and efficacy of ophthalmic topical Cn inhibitors.
This box summarizes key points contained in the article.
VKC is a bilateral, chronic inflammatory disorder of the palpebral and limbal regions, mainly affecting patients in their first and second decade of life. Its prevalence is higher in parts of Africa, Latin America and Asia. Population prevalence of 4 -- 5% has been reported among children in Africa [4]. Its predominant symptoms include ocular itching, tearing, mucous discharge, severe photophobia and foreign body sensation, with hallmark signs of upper tarsal conjunctiva papillary hyperplasia and infiltration of the limbal subconjunctival tissues forming nodules [5]. Its pathogenesis is not completely understood, but growing evidence suggests that in addition to the IgE-mediated type I hypersensitivity, cell-mediated mechanisms such as CD4 T cells may play a role in recruitment and activation of mast cells, eosinophils and B cells switching to the production of IgE. AKC is a bilateral chronic inflammation of the conjunctiva and cornea, mainly affecting patients in their adulthood. Complications of AKC include formation of giant cell papilla, conjunctival scarring, keratoconus, retinal detachment, and in the more severe cases, vision loss. The differentiating factor between nonsight-threatening allergic conjunctivitis and sight-threatening AKC may be T lymphocytes and eosinophils leading to formation of destructive enzymes, which are generally not present in SAC and PAC [2]. GPC is characterized by papillary hypertrophy of the superior tarsal conjunctiva, with papilla diameter typically > 3 mm, but it typically spares the cornea. Similar to AKC and VKC, cell-mediated process is implicated in its pathogenesis [6].
Pharmacodynamics of topical calcineurin inhibitors 2.
Cn plays an important role in the activation of T cell through a calcium-dependent pathway in which Cn activates nuclear factor of activated T cell protein (NF-ATp) via 544
dephosphorylation [7]. The NF-ATp is then translocated into the nucleus where it upregulates the expression of IL-2, which in turn, stimulates differentiation and growth of T cells. Cn inhibitors is a class of drugs that includes cyclosporine A (CsA), tacrolimus and pimecrolimus, which targets the cytoplasmic Cn pathway to induce immunosuppression. CsA is a hydrophobic, cyclic polypeptide consisting of 11 amino acids, originally derived from the fungus Tolypocladium inflatum. It inhibits Cn by binding to its receptor, cyclophilin. Systemic CsA is widely used in solid organ transplantation. Topical application of CsA was first used in ophthalmology to inhibit corneal allograft reaction in the early 1980s [8]. Since then, the use of topical Cn inhibitor for ocular diseases has dramatically increased. In 2003, a topical preparation of cyclosporine 0.05% ophthalmic solution, Restasis (Allergan, Inc., Irvine, CA, USA), was approved by the US FDA for use in the treatment of dry eyes. Animal model studies showed that topical CsA was effective in inhibiting eosinophil and mast cell-mediated allergic conjunctivitis in mice [9]. Off-label use for allergic conjunctivitis in the USA has increased since the initial approval. Cyclosporine 0.1% ophthalmic solution (Papilock Mini, Santen Pharmaceutical Co., Ltd, Grand Front Osaka Tower A, Ofuka-cho, Kita-ku, Osaka, Japan) was approved for the treatment of patients with allergic conjunctival disease in 2005 in Japan [10]. Tacrolimus is a 23-member macrolide lactone compound discovered in 1984 from a fermentation of broth soil with a bacterium, Streptomyces tsukubaensis. It binds to immunophilin FK-binding protein (FKBP-12), which in turn, inhibits Cn. Tacrolimus inhibits the release of histamine and other inflammatory mediators from basophils, and has a higher potency than CsA [11]. Topical tacrolimus ointment in 0.03 and 0.1% concentrations, Protopic (Astellas Pharma, Inc., Astellas Way Northbrook, IL, USA), was FDA-approved as a second-line agent for atopic dermatitis in the USA [12]. Topical ophthalmic ointment has been used in clinical trials and animal studies. Pimecrolimus is a naturally occurring antimicrobial (macrolactam), called ascomycin. The topical 0.1% form, Elidel (Novartis International AG, Novartis Corporation Corporate Communications, New York, NY, USA), was approved by the FDA in 2001 for use in mild-to-moderate atopic dermatitis [13]. Studies suggest that it is less effective compared to 0.1% tacrolimus and potent corticosteroids [14], which may be explained by its lesser potency when compared to tacrolimus [15]. In 2006, the FDA amended the approval of both topical tacrolimus and pimecrolimus with a boxed warning, which states that although a causal relationship had not been established, rare cases of malignancies (e.g., skin cancer, melanoma) have been reported in patients treated with topical Cn inhibitors [12,13]. However, topical Cn inhibitor agents for ophthalmic use have not been reported to be associated with increased malignancy risk at this time [16].
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis
3.
Pharmacokinetics
Pharmacokinetic properties of CsA as a lipophilic compound limit the benefit of topical therapy. The intraocular concentrations of topically applied CsA vary, but concentrations in aqueous humor are rather low, while high concentrations are achieved in the corneal epithelium [14,17]. Delivery vehicles such as collagen shields and a-cyclodextrin have improved bioavailability up to tenfold. More recently, CsA ophthalmic drops, such as Restasis (0.05% cyclosporine eye drop), using lipid emulsion formulations in castor oil have been shown to achieve greater ocular bioavailability and tolerability. In animal studies, topical administration of CsA emulsion was shown to have adequate absorption and retention into conjunctiva, cornea (up to 96 h) and lacrimal gland (up to 3 h) at concentrations sufficiently high to suppress inflammatory processes, with minimal systemic absorption [18]. In clinical trials of ophthalmic CsA emulsions for dry eyes, systemic levels of CsA were not detectable in patients receiving topical 0.05% CsA and were very low in patients receiving 0.1% CsA [19-21]. In one study, the mean trough CsA blood concentration from topical ophthalmic use of CsA emulsions was at least 750 times lower than the mean trough levels seen from those with systemic therapeutic use [19]. FK506 (tacrolimus) is not only lipophilic, like CsA, but also has a higher molecular weight (822 Da), which further limits its corneal penetration [22]. However, with the use of transport vehicles like cyclodextrins or liposomes, intraocular levels can be increased significantly, and its intraocular drug levels can be higher than those of CsA [22-24]. While the use of topical tacrolimus in treatment of atopic dermatitis has been well-established due to its excellent safety profile and minimal systemic absorption [25-27], studies examining the ophthalmic use of topical tacrolimus are less abundant. In one animal study by Yuan et al. [28], using 5% FK506 ocular suspension, the concentration of FK506 in the conjunctiva, cornea and sclera reached its highest level at 60 min after application, with the highest retention rate in cornea at 240 min. These findings suggest that the cornea, due to its avascularity, may serve as a reservoir for FK506. Similarly to CsA, the systemic blood concentration of FK506 was not detectable in this study. In an open-label study involving pediatric patients with allergic conjunctivitis, blood levels after 2 weeks of treatment with 0.03% tacrolimus ointment were reported as 0 in 5 eyes, 0.6 ng/ml and 0.9 ng/ml in 2 eyes and ‘> 1.5 ng/ml’ in 12 eyes [29]. Unlike systemic tacrolimus, which has many known interactions with CYP3A inhibitors, formal drug interactions between systemic oral drugs and topical tacrolimus have not been studied although it was hypothesized to be unlikely given the near zero systemic serum levels detected [12]. Despite the more prevalent use of topical pimecrolimus as skin preparation, its use as ophthalmic medication is still limited, except in few animal studies evaluating its effect in
keratoconjunctivitis sicca [30,31]. Studies involving topical tacrolimus for the treatment of allergic conjunctivitis have often used tacrolimus ointment for application on the eyelids, thereby exerting its effect on the conjunctivitis as well. The full pharmacokinetic data pertinent to human eye conditions have not yet been fully studied. 4.
Safety profile
Despite the significant nephrotoxicity, hepatotoxicity and increased infection risk associated with systemic CsA, multiple studies have shown topical CsA to be generally safe with few serious side-effects [19,21,32]. In a Phase III clinical trial for dry eye using 0.1% topical CsA emulsion for 3 years, treatment-related adverse events were found in 22.1% of patients, including burning eye (10.9% of patients), stinging eye (3.9%), conjunctival hyperemia (3.4%), pruritus (2.2%), epiphora (1.9%), photophobia (1.7%), foreign body sensation (1.5%) and eye discharge (1.2%) [21]. In one prospective observational trial of 594 patients, infectious corneal complications were observed in 5 patients, including 2 cases of bacterial corneal ulcer and 3 cases of herpetic keratitis. However, all involved patients were concomitantly treated using topical steroids [10]. Similarly, serious systemic sideeffects of ophthalmic topical use of tacrolimus have not been observed [29,33]. In a randomized controlled trial of ophthalmic suspension of tacrolimus in patients with severe allergic conjunctivitis [33], the most frequent tacrolimusrelated adverse event was ocular irritation (42.9%), but it was otherwise well-tolerated. One patient in the tacrolimus group developed corneal lesion suspected to be due to herpes simplex virus (HSV), although no precise diagnosis was performed. There have been no reports of increased incidence of HSV infection in patients treated with tacrolimus ointment for atopic dermatitis in long-term follow-up studies. An openlabel study using 0.03% topical tacrolimus eye drops for the treatment of dry eyes in patients with graft-versus-host disease have similarly shown ophthalmic tacrolimus drops to be safe without significant adverse events, although the study size was too small to identify the complete safety profile [34]. The adverse effects of pimecrolimus ophthalmic drops are limited to select studies involving canine, which showed variable effects including excessive lacrimation, conjunctival hyperemia and discomfort, but no systemic effects were examined [30,31]. Evidence for increased cancer risk is much more limited for Cn inhibitors, azathioprine and TNF-inhibitors. It is likely that there is no or little increase in the absolute risk of cancer with these agents in an inflammatory eye diseases setting. 5.
Clinical efficacy
Efficacy of cyclosporine Secondary to its widespread use in the treatment of dry eyes, topical ophthalmic CsA has been used in multiple clinical 5.1
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
545
X. C. Wan & V. Dimov
trials for the treatment of allergic conjunctivitis, with generally positive results. In a prospective observational study in Japan of 594 patients with VKC and AKC, 0.1% topical CsA eye drops significantly reduced signs and symptoms from month 1 through month 6 of use [10]. In a randomized, multi-center trial in patients with AKC requiring topical steroid drops, 0.05% CsA reduced signs and composite symptoms compared to placebo [35]. However, in another randomized controlled trial comparing 0.05% topical CsA to placebo, the effect of CsA was not statistically significant [36]. In a recently published meta-analysis of seven randomized controlled trials [37] comparing topical ophthalmic CsA to placebo in patients with allergic conjunctivitis (AKC, VKC or both), topical CsA was more effective in alleviating signs (as judged by clinicians) and symptoms (self-reported) of allergic conjunctivitis while maintaining similar safety profile to placebo. Of the three studies that recruited patients with steroid-dependent allergic conjunctivitis, two reported reduction in the use of steroid eye drops. The use of CsA ophthalmic drops was also tested in pediatrics patients. In an observational trial of 7 pediatric patients with severe allergic conjunctivitis despite the use of topical steroids, 0.05% topical CsA decreased the symptoms and signs after 6 months and eliminated the need for steroids in 6 patients [38]. However, in a randomized controlled study comparing 2% CsA with topical steroids in patients with allergic conjunctivitis in Rwanda, there was no statistical difference [36]. Combined, these studies suggest that ophthalmic CsA drops are more effective compared to placebo, and may be equally efficacious to topical steroids. Topical CsA may be a promising, safe alternative for reducing or eliminating the need to chronic topical steroid in patients with severe allergic conjunctivitis. However, larger randomized controlled trials may be needed to confirm the findings, especially in pediatric patients.
Effective dose of cyclosporine The CsA ophthalmic drops dose in clinical studies varies from 0.05 to 0.2%, although only the 0.05% dosing is commercially available in the US. The minimum effective dose for various manifestations of allergic conjunctivitis has not been extensively studied. In one study of AKC patients requiring topical steroid drops, 0.05% CsA reduced signs and composite symptoms compared to placebo [35]. In patients with VKC, a study comparing 1 -- 1.25% topical CsA suggested that 1% may be the minimal effective concentration dose for treatment regimen for VKC [39]. In a randomized controlled study using 2% topical CsA in maize oil, there was a significant steroid sparing effect in patients with AKC, but there were significantly more side-effects compared to placebo, including transient blurry vision and stinging upon distillation [40]. These studies suggest that 0.05 -- 1% may be an effective dose for the treatment of AKC and VKC. 5.2
546
Efficacy of tacrolimus While not as extensive, clinical studies involving topical tacrolimus for the treatment of allergic conjunctivitis have been performed. In a 4-week open-label trial of 0.1% topical tacrolimus ointment in 10 pediatric patients with recalcitrant VKC, there was a 20% reduction in symptom score, and reduction in tarsal papilla size, chemosis, conjunctival swelling and injection compared to baseline [41]. In another prospective trial of 10 patients with VKC, both adults and children, the use of 0.01% topical tacrolimus drops in salt suspension for 1 month decreased signs and symptoms, although discontinuing the treatment led to a rapid recurrence of the symptoms [42]. Other small retrospective and case studies using 0.02 -- 0.1% of topical tacrolimus ointment have also shown promising efficacy in the treatment of AKC [43,44], as well as papillary conjunctivitis [45]. Ohashi et al. reported a multicentered, randomized controlled trial in Japan, which compared 0.01% tacrolimus suspension to placebo in 56 patients with severe allergic conjunctivitis (AKC and VKC) who had failed topical steroids. This study showed that after 4 weeks of treatment, there was an improvement in giant papillae (p = 0.001) and corneal involvement (p = 0.005), as well as symptoms of itching, discharge, hyperemia, lacrimation and foreign body sensation in the treatment group compared to the placebo group [46]. 5.3
Effective dose of tacrolimus Doses of tacrolimus used to treat severe allergic conjunctivitis vary from 0.02 to 0.1%, with variations in formulations ranging from aqueous solutions to skin ointment used for treatment of allergic dermatitis (applied to the eyelids). Many have demonstrated success in the treatment of refractory allergic conjunctivitis. Most of these studies were small, open-label trials or retrospective studies. Optimal doses for treatment of different forms of allergic conjunctivitis have yet to be established. 5.4
Pimecrolimus While there have been some studies in the literature examining the role of topical pimecrolimus in skin conditions, its use as an ophthalmic topical agent is extremely limited, and was mainly evaluated in animal studies [30]. 5.5
Comparison of efficacy of topical calcineurin inhibitors
5.6
Very few studies have directly compared the efficacy of one topical Cn inhibitor against another in the treatment of allergic conjunctivitis. One randomized controlled trial from Thailand compared 0.1% tacrolimus to 2% cyclosporine in 24 pediatric patients with VKC and showed improvement in signs and symptoms compared to baseline in both groups, but no statistically significant difference in the efficacy and side-effect profile between the two groups [47]. Both groups were treated with tacrolimus 0.1% for 4 weeks, following
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis
treatment with either cyclosporine or tacrolimus for 8 weeks. In an open-enrollment animal study involving canines, 1% pimecrolimus eye drop was shown to be more effective in reducing symptoms of keratoconjunctivitis sicca compared to cyclosporine ointment, but that trial was limited to symptoms of dry eyes [48]. 6.
Conclusion
There is increasing literature in the use of ophthalmic topical Cn inhibitors for treatment of severe forms of allergic conjunctivitis involving cell-mediated pathogenesis. Ophthalmic use of topical Cn inhibitors such as cyclosporine and tacrolimus has been shown to be safe with minimal systemic sideeffects, and they may prove to be effective steroid-sparing agents for use in patients with refractory allergic conjunctivitis. Smaller clinical trials generally show that topical CsA is effective in reducing signs and symptoms of allergic conjunctivitis, often reducing the need for topical steroids. Similar efficacy was seen in studies using ophthalmic tacrolimus drops, although the data are less numerous. Little is known about the effect of ophthalmic pimecrolimus drops in humans. 7.
Expert opinion
The prevalence of allergic conjunctivitis is estimated to be 20 -- 30% of the general population. In the selected population of patients with IgE-mediated allergy, 40 -- 80% has ocular symptoms. Allergic conjunctivitis is a complex condition with several subtypes and can be treated with a variety of medications, including topical antihistamines, mast cell stabilizers, NSAIDs, Cn inhibitors and corticosteroids. Topical corticosteroids are considered the mainstay of treatment for severe allergic conjunctivitis, but prolonged use has been associated with elevated intraocular pressure, glaucoma, cataract and increased susceptibility to infections. With the emergence of topical ophthalmic Cn inhibitors for a wide variety of indications ranging from dry eyes, to allergic conjunctivitis, to posttransplantation immunosuppression, there has been a rising interest in the research surrounding both safety and efficacy of topical Cn inhibitors in adults and children. Pharmacokinetic studies clearly show that Cn inhibitors are lipophilic compounds and therefore delivery vehicles such as collagen shields, a-cyclodextrin and lipid emulsion formulations must be used to achieve adequate absorption and retention
into conjunctiva, cornea and lacrimal glands. Systemic blood concentrations are not detectable with topical Cn inhibitor therapy. Unlike systemic Cn inhibitors, which have significant side-effects, ophthalmic topical Cn inhibitors, such cyclosporine and tacrolimus, have generally been shown to be safe for short-term use, with minimal systemic absorption and toxicity. Most reported adverse reactions were limited to localized discomfort and stinging sensation during instillation of the ophthalmic medication. While only few incidences of possible viral or bacterial infection involving the ocular surface have been reported, ongoing close monitoring of the patients who are on topical Cn inhibitors should be recommended. For patients with severe, refractory forms of allergic conjunctivitis such as VKC, ACK and GPC that have cell-mediated pathogenesis, topical Cn inhibitors are a promising treatment alternative for both its symptoms relief and steroid-steroid effects by controlling and maintaining quiescence of the inflammatory state. The safety profile and efficacy data for topical cyclosporine are more robust compared to that of tacrolimus and pimecrolimus, although larger, randomized controlled trials will be needed for all three agents to further elucidate the long-term safety and efficacy of these agents. Indeed, one of the weaknesses of the reported clinical trials is the short duration of therapy. Post-marketing surveillance can be helpful in detecting previously unreported adverse effects but such reports are not as robust due to the nature of the surveillance process. The ultimate goal of the treatment of allergic conjunctivitis is full control of symptoms with the lowest dose that is proven to be safe for long-term use. However, the minimal concentration of topical Cn inhibitors needed to most effectively control the signs and symptoms of allergic conjunctivitis while minimizing its side-effects has not been extensively studied and will likely vary with the different forms of allergic conjunctivitis and disease severity. With more randomized controlled trials involving larger sample size and long-term follow up to establish both efficacy and safety, ophthalmic Cn inhibitors offer exciting treatment possibilities to decrease the morbidity associated with refractory allergic conjunctivitis.
Declaration of interest The authors have no competing interests to declare and have received no funding in preparation of the manuscript.
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
547
X. C. Wan & V. Dimov
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Kari O, Saari KM. Updates in the treatment of ocular allergies. J Asthma Allergy 2010;3:149-58
2.
Sy H, Bielory L. Atopic keratoconjunctivitis. Allergy Asthma Proc 2013;34(1):33-41
3.
Bielory L. Ocular allergy treatment. Immunol Allergy Clin North Am 2008;28:189-224; vii
4.
De Smedt S, Nkhurikiye J, Fonteyne Y, et al. Vernal keratoconjunctivitis in school children in Rwanda and its association with socio-economic status: a population-based survey. Am J Trop Med Hyg 2011;85:711-17
information). Astellas Pharma US, Inc; Deerfield (IL); 2011 13.
Elidel (Pimecrolimus) cream 1 % (US prescribing information). Novartis Pharmaceuticals Corporation; East Hanover (NJ); 2001
14.
Ashcroft DM, Chen LC, Garside R, et al. Topical pimecrolimus for eczema. Cochrane Database Syst Rev 2007;(4):CD005500
15.
Gutfreund K, Bienias W, Sczewczyk A, et al. Topical calcineurin inhibitors in dermatology. Part I: properties, methods, and effectiveness of drug use. Postepy Dermatol Alergol 2013;30(3):165-9
16.
Kempen JH, Gangaputra S, Daniel E, et al. Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: acritical assessment of the evidence. Am J Ophthalmol 2008;146(6):802-12
.
administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 2005;112(10):1790-4 This paper was noteworthy in demonstrating the longer-term safety profile of topical CsA.
22.
Pleyer U, Lutz S, Jusko WJ, et al. Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. Invest Ophthalmol Vis Sci 1993;34:2737-42
23.
Bertelmann E, Pleyer U. Immunomodulatory therapy in ophthalmology -- is there a place for topical application? Ophthalmologica 2004;218:359-67
24.
Benelli U, Lepri A, Del Tacca M, et al. FK-506 delays corneal graft rejection in a model of corneal xenotransplantation. J Ocul Pharmacol Ther 1996;12:425-31
25.
Ruzicka T, Bieber T, Schopf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. European tacrolimus multicenter atopic dermatitis study group. N Engl J Med 1997;337:816-21
5.
De Smedt S, Wildner G, Kestelyn P. Vernal keratoconjunctivitis: an update. Br J Ophthalmol 2013;97(1):9-14
6.
La Rosa M, Lionetti E, Reibaldi M, et al. Allergic conjunctivitis: a comprehensive review of the literature. Ital J Pediatr 2013;39:18
17.
McCaffrey PG, Perrino BA, Soderline TR, et al. NF-ATp, a T lymphocyte DNA-binding protein that is a target for calcineurin and immunosuppressive drugs. J Biol Chem 1993;268(5):3747-52
Lallemand F, Felt-Baeyens O, Besseghir K, et al. Cyclosporine A delivery to the eye: a pharmaceutical challenge. Eur J Pharm Biopharm 2003;56(3):307-18
26.
18.
Acheampong AA, Shackleton M, Tang-Liu DD, et al. Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs. Curr Eye Res 1999;18(2):91-103
Boguniewicz M, Fiedler VC, Raimer S, et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 1998;102:637-44
27.
19.
Small DS, Acheampong A, Reis B, et al. Blood concentrations of cyclosporin A during long-term treatment with cyclosporin a ophthalmic emulsions inpatients with moderate to severe dry eye disease. J Ocul Pharmacol Ther 2002;18(5):411-18 This paper was noteworthy in studying the systemic absorption of topical CsA.
Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol 2013;131(2):295-9
28.
Yuan J, Zhai JJ, Chen JQ, et al. Preparation of 0.05% FK506 suspension eyedrops and its pharmacokinetics after topical ocular administration. J Ocul Pharmacol Ther 2009;25(4):345-50
29.
Attas-Fox L, Barkana Y, Iskhakov V, et al. Topical tacrolimus 0.03% ointment for intractable allergic conjunctivitis: an open-label pilot study. Curr Eye Res 2008;33(7):545-9
30.
Nell B, Walde J, Billich A, et al. The effect of topical pimecrolimus on keratoconjunctivitis sicca and chronic superficial keratitis in dogs: results from an exploratory study. Vet Ophthalmol 2005;8(1):39-46
31.
Ofri R, Lambrou GN, Allgoewer I, et al. Clinical evaluation of pimecrolimus eye drops for treatment of canine
7.
8.
Hunter PA, Wilhelmus KR, Rice NS, et al. Cyclosporin a applied topically to the recipient eye inhibits corneal graft rejection. Clin Exp Immunol 1981;45(1):173-7
9.
Whitcup SM, Chan CC, Luyo DA, et al. Topical cyclosporine inhibits mast cell-mediated conjunctivitis. Invest Ophthalmol Vis Sci 1996;37(13):2686-93
10.
Ebihara N, Ohashi Y, Uchio E, et al. A large prospective observational study of novel cyclosporine 0.1% aqueous ophthalmic solution in the treatment of severe allergic conjunctivitis. J Ocul Pharmacol Ther 2009;25(4):365-72
11.
12.
548
DePaulis A, Cirillo R, Ciccarelli A, et al. FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells. J Immunol 1991;146(7):2374-81 Protopic (Tacrolimus) ointment 0.03 % and ointment 0.1 % (US prescribing
.
20.
.
21.
Sall K, Stevenson OD, Mudorf TK, et al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA phase 3 study group. Ophthalmology 2000;107(4):631-9 This paper was noteworthy in establishing the efficacy and safety profile of topical CsA. Barber LD, Pflugfelder SC, Tauber J, et al. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis
32.
33.
34.
38.
Tang-Liu DD, Acheampong A. Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye. Clin Pharmacokinet 2005;44(3):247-61
Ozcan AA, Ersoz TR, Dulger E. Management of severe allergic conjunctivitis with topical cyclosporin A 0.05% eyedrops. Cornea 2007;26(9):1035-8
39.
Spadavecchia L, Fanelli P, Tesse R, et al. Efficacy of 1.25% and 1% topical cyclosporine in the treatment of severe vernal keratoconjunctivitis in childhood. Pediatr Allergy Immunol 2006;17(7):527-32
Ohashi Y, Ebihara N, Fujishima H, et al. A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis. J Ocul Pharmacol Ther 2010;26(2):165-74 Sanz-Marco E, Udaondo P, Garcı´a-Delpech S, et al. Treatment of refractory dry eye associated with graft versus host disease with 0.03% tacrolimus eyedrops. J Ocul Pharmacol Ther 2013;29(8):776-83
35.
Akpek EK, Dart JK, Watson S, et al. A randomized trial of topical cyclosporin 0.05% in topical steroid-resistant atopic keratoconjunctivitis. Ophthalmology 2004;111:476-82
36.
Daniell M, Constantinou M, Vu HT, et al. Randomised controlled trial of topical ciclosporin A in steroid dependent allergic conjunctivitis. Br J Ophthalmol 2006;90(4):461-4
37.
..
Wan KH, Chen LJ, Rong SS, et al. Topical cyclosporine in the treatment of allergic conjunctivitis: a meta-analysis. Ophthalmology 2013, doi:pii: S0161-6420(13)00329-1. 10.1016/j. ophtha.2013.03.044 This paper is particularly noteworthy in that it is a meta-analysis that examines the randomized controlled trials of topical CsA in allergic
study. Acta Ophthalmol Scand 2006;84(5):693-5
conjunctivitis. The evidence it provides is significant.
keratoconjunctivitis sicca: a comparison with cyclosporine A. Vet J 2009;179(1):70-7
40.
Hingorani M, Moodaley L, Calder VL, et al. A randomized, placebo-controlled trial of topical cyclosporin A in steroiddependent atopic keratoconjunctivitis. Ophthalmology 1998;105(9):1715-20
41.
Vichyanond P, Tantimongkolsuk C, Dumrongkigchaiporn P, et al. Vernal keratoconjunctivitis: result of a novel therapy with 0.1% topical ophthalmic FK-506 ointment. J Allergy Clin Immunol 2004;113(2):355-8
42.
Kheirkhah A, Zavareh MK, Farzbod F, et al. Topical 0.005% tacrolimus eye drop for refractory vernal keratoconjunctivitis. Eye (Lond) 2011;25:872-80
43.
Rikkers SM, Holland GN, Drayton GE, et al. Topical tacrolimus treatment of atopic eyelid disease. Am J Ophthalmol 2003;135(3):297-302
44.
Virtanen HM, Reitamo S, Kari M, Kari O. Effect of 0.03% tacrolimus ointment on conjunctival cytology in patients with severe atopic blepharoconjunctivitis: a retrospective
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
45.
Kymionis GD, Goldman D, Ide T, Yoo SH. Tacrolimus ointment 0.03% in the eye for treatment of giant papillary conjunctivitis. Cornea 2008;27(2):228-9
46.
Ohashi Y, Ebihara N, Fujishima H, et al. A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1 % in severe allergic conjunctivitis. J Ocul Pharmacol Ther 2010;26:165-74
47.
Labcharoenwongs P, Jirapongsananuruk O, Visitsunthorn N, et al. A double-masked comparison of 0.1% tacrolimus ointment and 2% cyclosporine eye drops in the treatment of vernal keratoconjunctivitis in children. Asian Pac J Allergy Immunol 2012;30:177-84
48.
Ofri R, Lambrou GN, Allgoewer I, et al. Clinical evaluation of pimecrolimus eye drops for treatment of canine keratoconjunctivitis sicca: a comparison with cyclosporine A. Vet J 2009;179(1):70-7
Affiliation
Xiao Chloe Wan1 MD & Vesselin Dimov†2 MD † Author for correspondence 1 University of Chicago, Department of Internal Medicine, 5841 South Maryland Ave MC 7082, Chicago, IL 60637, USA 2 Assistant Professor of Pediatrics and Medicine, University of Chicago, Section of Allergy, Asthma and Immunology, 5841 South Maryland Ave MC 4064, Chicago, IL 60637, USA Tel: +1 773 234 7731; E-mail: [email protected]
549
ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis Xiao Chloe Wan & Vesselin Dimov To cite this article: Xiao Chloe Wan & Vesselin Dimov (2014) Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis, Expert Opinion on Drug Metabolism & Toxicology, 10:4, 543-549, DOI: 10.1517/17425255.2014.884070 To link to this article: https://doi.org/10.1517/17425255.2014.884070
Published online: 03 Feb 2014.
Submit your article to this journal
Article views: 188
View related articles
View Crossmark data
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iemt20
Review
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis 1.
Introduction
2.
Pharmacodynamics of topical calcineurin inhibitors
3.
Pharmacokinetics
4.
Safety profile
5.
Clinical efficacy
6.
Conclusion
7.
Expert opinion
Xiao Chloe Wan & Vesselin Dimov† †
University of Chicago, Department of Pediatrics and Medicine, Section of Allergy, Asthma and Immunology, Chicago, IL, USA
Introduction: Topical calcineurin (Cn) inhibitors delivered via ophthalmic drop is emerging as a potential treatment for severe, immune-mediated forms of allergic conjunctivitis, such as vernal keratoconjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis. Areas covered: This article is based on a comprehensive literature search, with information taken from meta-analyses, systematic reviews, treatment guidelines and clinical studies in children and adults. The articles that have been selected evaluate the use of topical Cn inhibitors and their role in the treatment of allergic conjunctivitis. Expert opinion: Ophthalmic topical Cn inhibitors have been shown to be safe for short-term use, with minimal systemic absorption and toxicity. For patients with severe, refractory forms of allergic conjunctivitis, topical Cn inhibitors offer a promising treatment option and an alternative to steroidal therapies. The safety profile and efficacy data for topical cyclosporine are more robust compared to that of tacrolimus and pimecrolimus, although larger trials will be needed for all three agents. With more randomized controlled trials involving larger sample sizes and long-term follow-up to establish both efficacy and safety, ophthalmic Cn inhibitors offer exciting treatment possibilities for the prevention of morbidity associated with refractory allergic conjunctivitis. Keywords: allergic conjunctivitis, cyclosporine, tacrolimus, topical calcineurin inhibitors Expert Opin. Drug Metab. Toxicol. (2014) 10(4):543-549
1.
Introduction
Approximately one-third of the world’s population is affected by some form of allergic disease, and of those, 40 -- 80% have ocular allergic symptoms [1]. Allergic conjunctivitis can be divided into five sub-categories: seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC) [2]. SAC and PAC are caused by IgE reaction to environmental airborne allergens that specifically activate mast cell to release histamine, thus triggering symptoms such as eye irritation, itchiness, dryness and conjunctival injection. SAC and PAC are considered milder from the symptomatic perspective, and can typically be controlled with mast cell stabilizers and antihistamine agents. VKC, AKC and GPC are rarer forms of allergic conjunctivitis, and are typically lymphocyte cell-mediated in addition to IgE-mediated, with more severe symptoms and significant long-term consequences, often requiring topical steroids for control. However, prolonged use of topical steroids are not without its side effects, including elevated intraocular pressure, development of cataracts and increased susceptibility to microbial infection that can be vision threatening [3]. Thus, many of the topical calcineurin (Cn) inhibitors are used to treat VKC, AKC and GPC, with the goals of better symptom control and tapering of topical steroids. 10.1517/17425255.2014.884070 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
543
X. C. Wan & V. Dimov
Article highlights. .
.
.
.
.
Ophthalmic topical calcineurin (Cn) inhibitors such as cyclosporine and tacrolimus have been shown to be safe for short-term use with little systemic absorption and toxicity. Most common side-effects include burning and discomfort upon distillation and are generally well tolerated, with few incidences of possible ocular surface viral or bacterial infection. Small clinic studies suggest that ophthalmic cyclosporine drops are more effective compared to placebo and may be equally efficacious to topical steroids at relieving symptoms of severe allergic conjunctivitis. Ophthalmic tacrolimus drops are less readily available, but may also be effective at relieving symptoms of severe allergic conjunctivitis. Larger, randomized controlled trials will be needed to better examine the long-term safety profile and efficacy of ophthalmic topical Cn inhibitors.
This box summarizes key points contained in the article.
VKC is a bilateral, chronic inflammatory disorder of the palpebral and limbal regions, mainly affecting patients in their first and second decade of life. Its prevalence is higher in parts of Africa, Latin America and Asia. Population prevalence of 4 -- 5% has been reported among children in Africa [4]. Its predominant symptoms include ocular itching, tearing, mucous discharge, severe photophobia and foreign body sensation, with hallmark signs of upper tarsal conjunctiva papillary hyperplasia and infiltration of the limbal subconjunctival tissues forming nodules [5]. Its pathogenesis is not completely understood, but growing evidence suggests that in addition to the IgE-mediated type I hypersensitivity, cell-mediated mechanisms such as CD4 T cells may play a role in recruitment and activation of mast cells, eosinophils and B cells switching to the production of IgE. AKC is a bilateral chronic inflammation of the conjunctiva and cornea, mainly affecting patients in their adulthood. Complications of AKC include formation of giant cell papilla, conjunctival scarring, keratoconus, retinal detachment, and in the more severe cases, vision loss. The differentiating factor between nonsight-threatening allergic conjunctivitis and sight-threatening AKC may be T lymphocytes and eosinophils leading to formation of destructive enzymes, which are generally not present in SAC and PAC [2]. GPC is characterized by papillary hypertrophy of the superior tarsal conjunctiva, with papilla diameter typically > 3 mm, but it typically spares the cornea. Similar to AKC and VKC, cell-mediated process is implicated in its pathogenesis [6].
Pharmacodynamics of topical calcineurin inhibitors 2.
Cn plays an important role in the activation of T cell through a calcium-dependent pathway in which Cn activates nuclear factor of activated T cell protein (NF-ATp) via 544
dephosphorylation [7]. The NF-ATp is then translocated into the nucleus where it upregulates the expression of IL-2, which in turn, stimulates differentiation and growth of T cells. Cn inhibitors is a class of drugs that includes cyclosporine A (CsA), tacrolimus and pimecrolimus, which targets the cytoplasmic Cn pathway to induce immunosuppression. CsA is a hydrophobic, cyclic polypeptide consisting of 11 amino acids, originally derived from the fungus Tolypocladium inflatum. It inhibits Cn by binding to its receptor, cyclophilin. Systemic CsA is widely used in solid organ transplantation. Topical application of CsA was first used in ophthalmology to inhibit corneal allograft reaction in the early 1980s [8]. Since then, the use of topical Cn inhibitor for ocular diseases has dramatically increased. In 2003, a topical preparation of cyclosporine 0.05% ophthalmic solution, Restasis (Allergan, Inc., Irvine, CA, USA), was approved by the US FDA for use in the treatment of dry eyes. Animal model studies showed that topical CsA was effective in inhibiting eosinophil and mast cell-mediated allergic conjunctivitis in mice [9]. Off-label use for allergic conjunctivitis in the USA has increased since the initial approval. Cyclosporine 0.1% ophthalmic solution (Papilock Mini, Santen Pharmaceutical Co., Ltd, Grand Front Osaka Tower A, Ofuka-cho, Kita-ku, Osaka, Japan) was approved for the treatment of patients with allergic conjunctival disease in 2005 in Japan [10]. Tacrolimus is a 23-member macrolide lactone compound discovered in 1984 from a fermentation of broth soil with a bacterium, Streptomyces tsukubaensis. It binds to immunophilin FK-binding protein (FKBP-12), which in turn, inhibits Cn. Tacrolimus inhibits the release of histamine and other inflammatory mediators from basophils, and has a higher potency than CsA [11]. Topical tacrolimus ointment in 0.03 and 0.1% concentrations, Protopic (Astellas Pharma, Inc., Astellas Way Northbrook, IL, USA), was FDA-approved as a second-line agent for atopic dermatitis in the USA [12]. Topical ophthalmic ointment has been used in clinical trials and animal studies. Pimecrolimus is a naturally occurring antimicrobial (macrolactam), called ascomycin. The topical 0.1% form, Elidel (Novartis International AG, Novartis Corporation Corporate Communications, New York, NY, USA), was approved by the FDA in 2001 for use in mild-to-moderate atopic dermatitis [13]. Studies suggest that it is less effective compared to 0.1% tacrolimus and potent corticosteroids [14], which may be explained by its lesser potency when compared to tacrolimus [15]. In 2006, the FDA amended the approval of both topical tacrolimus and pimecrolimus with a boxed warning, which states that although a causal relationship had not been established, rare cases of malignancies (e.g., skin cancer, melanoma) have been reported in patients treated with topical Cn inhibitors [12,13]. However, topical Cn inhibitor agents for ophthalmic use have not been reported to be associated with increased malignancy risk at this time [16].
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis
3.
Pharmacokinetics
Pharmacokinetic properties of CsA as a lipophilic compound limit the benefit of topical therapy. The intraocular concentrations of topically applied CsA vary, but concentrations in aqueous humor are rather low, while high concentrations are achieved in the corneal epithelium [14,17]. Delivery vehicles such as collagen shields and a-cyclodextrin have improved bioavailability up to tenfold. More recently, CsA ophthalmic drops, such as Restasis (0.05% cyclosporine eye drop), using lipid emulsion formulations in castor oil have been shown to achieve greater ocular bioavailability and tolerability. In animal studies, topical administration of CsA emulsion was shown to have adequate absorption and retention into conjunctiva, cornea (up to 96 h) and lacrimal gland (up to 3 h) at concentrations sufficiently high to suppress inflammatory processes, with minimal systemic absorption [18]. In clinical trials of ophthalmic CsA emulsions for dry eyes, systemic levels of CsA were not detectable in patients receiving topical 0.05% CsA and were very low in patients receiving 0.1% CsA [19-21]. In one study, the mean trough CsA blood concentration from topical ophthalmic use of CsA emulsions was at least 750 times lower than the mean trough levels seen from those with systemic therapeutic use [19]. FK506 (tacrolimus) is not only lipophilic, like CsA, but also has a higher molecular weight (822 Da), which further limits its corneal penetration [22]. However, with the use of transport vehicles like cyclodextrins or liposomes, intraocular levels can be increased significantly, and its intraocular drug levels can be higher than those of CsA [22-24]. While the use of topical tacrolimus in treatment of atopic dermatitis has been well-established due to its excellent safety profile and minimal systemic absorption [25-27], studies examining the ophthalmic use of topical tacrolimus are less abundant. In one animal study by Yuan et al. [28], using 5% FK506 ocular suspension, the concentration of FK506 in the conjunctiva, cornea and sclera reached its highest level at 60 min after application, with the highest retention rate in cornea at 240 min. These findings suggest that the cornea, due to its avascularity, may serve as a reservoir for FK506. Similarly to CsA, the systemic blood concentration of FK506 was not detectable in this study. In an open-label study involving pediatric patients with allergic conjunctivitis, blood levels after 2 weeks of treatment with 0.03% tacrolimus ointment were reported as 0 in 5 eyes, 0.6 ng/ml and 0.9 ng/ml in 2 eyes and ‘> 1.5 ng/ml’ in 12 eyes [29]. Unlike systemic tacrolimus, which has many known interactions with CYP3A inhibitors, formal drug interactions between systemic oral drugs and topical tacrolimus have not been studied although it was hypothesized to be unlikely given the near zero systemic serum levels detected [12]. Despite the more prevalent use of topical pimecrolimus as skin preparation, its use as ophthalmic medication is still limited, except in few animal studies evaluating its effect in
keratoconjunctivitis sicca [30,31]. Studies involving topical tacrolimus for the treatment of allergic conjunctivitis have often used tacrolimus ointment for application on the eyelids, thereby exerting its effect on the conjunctivitis as well. The full pharmacokinetic data pertinent to human eye conditions have not yet been fully studied. 4.
Safety profile
Despite the significant nephrotoxicity, hepatotoxicity and increased infection risk associated with systemic CsA, multiple studies have shown topical CsA to be generally safe with few serious side-effects [19,21,32]. In a Phase III clinical trial for dry eye using 0.1% topical CsA emulsion for 3 years, treatment-related adverse events were found in 22.1% of patients, including burning eye (10.9% of patients), stinging eye (3.9%), conjunctival hyperemia (3.4%), pruritus (2.2%), epiphora (1.9%), photophobia (1.7%), foreign body sensation (1.5%) and eye discharge (1.2%) [21]. In one prospective observational trial of 594 patients, infectious corneal complications were observed in 5 patients, including 2 cases of bacterial corneal ulcer and 3 cases of herpetic keratitis. However, all involved patients were concomitantly treated using topical steroids [10]. Similarly, serious systemic sideeffects of ophthalmic topical use of tacrolimus have not been observed [29,33]. In a randomized controlled trial of ophthalmic suspension of tacrolimus in patients with severe allergic conjunctivitis [33], the most frequent tacrolimusrelated adverse event was ocular irritation (42.9%), but it was otherwise well-tolerated. One patient in the tacrolimus group developed corneal lesion suspected to be due to herpes simplex virus (HSV), although no precise diagnosis was performed. There have been no reports of increased incidence of HSV infection in patients treated with tacrolimus ointment for atopic dermatitis in long-term follow-up studies. An openlabel study using 0.03% topical tacrolimus eye drops for the treatment of dry eyes in patients with graft-versus-host disease have similarly shown ophthalmic tacrolimus drops to be safe without significant adverse events, although the study size was too small to identify the complete safety profile [34]. The adverse effects of pimecrolimus ophthalmic drops are limited to select studies involving canine, which showed variable effects including excessive lacrimation, conjunctival hyperemia and discomfort, but no systemic effects were examined [30,31]. Evidence for increased cancer risk is much more limited for Cn inhibitors, azathioprine and TNF-inhibitors. It is likely that there is no or little increase in the absolute risk of cancer with these agents in an inflammatory eye diseases setting. 5.
Clinical efficacy
Efficacy of cyclosporine Secondary to its widespread use in the treatment of dry eyes, topical ophthalmic CsA has been used in multiple clinical 5.1
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
545
X. C. Wan & V. Dimov
trials for the treatment of allergic conjunctivitis, with generally positive results. In a prospective observational study in Japan of 594 patients with VKC and AKC, 0.1% topical CsA eye drops significantly reduced signs and symptoms from month 1 through month 6 of use [10]. In a randomized, multi-center trial in patients with AKC requiring topical steroid drops, 0.05% CsA reduced signs and composite symptoms compared to placebo [35]. However, in another randomized controlled trial comparing 0.05% topical CsA to placebo, the effect of CsA was not statistically significant [36]. In a recently published meta-analysis of seven randomized controlled trials [37] comparing topical ophthalmic CsA to placebo in patients with allergic conjunctivitis (AKC, VKC or both), topical CsA was more effective in alleviating signs (as judged by clinicians) and symptoms (self-reported) of allergic conjunctivitis while maintaining similar safety profile to placebo. Of the three studies that recruited patients with steroid-dependent allergic conjunctivitis, two reported reduction in the use of steroid eye drops. The use of CsA ophthalmic drops was also tested in pediatrics patients. In an observational trial of 7 pediatric patients with severe allergic conjunctivitis despite the use of topical steroids, 0.05% topical CsA decreased the symptoms and signs after 6 months and eliminated the need for steroids in 6 patients [38]. However, in a randomized controlled study comparing 2% CsA with topical steroids in patients with allergic conjunctivitis in Rwanda, there was no statistical difference [36]. Combined, these studies suggest that ophthalmic CsA drops are more effective compared to placebo, and may be equally efficacious to topical steroids. Topical CsA may be a promising, safe alternative for reducing or eliminating the need to chronic topical steroid in patients with severe allergic conjunctivitis. However, larger randomized controlled trials may be needed to confirm the findings, especially in pediatric patients.
Effective dose of cyclosporine The CsA ophthalmic drops dose in clinical studies varies from 0.05 to 0.2%, although only the 0.05% dosing is commercially available in the US. The minimum effective dose for various manifestations of allergic conjunctivitis has not been extensively studied. In one study of AKC patients requiring topical steroid drops, 0.05% CsA reduced signs and composite symptoms compared to placebo [35]. In patients with VKC, a study comparing 1 -- 1.25% topical CsA suggested that 1% may be the minimal effective concentration dose for treatment regimen for VKC [39]. In a randomized controlled study using 2% topical CsA in maize oil, there was a significant steroid sparing effect in patients with AKC, but there were significantly more side-effects compared to placebo, including transient blurry vision and stinging upon distillation [40]. These studies suggest that 0.05 -- 1% may be an effective dose for the treatment of AKC and VKC. 5.2
546
Efficacy of tacrolimus While not as extensive, clinical studies involving topical tacrolimus for the treatment of allergic conjunctivitis have been performed. In a 4-week open-label trial of 0.1% topical tacrolimus ointment in 10 pediatric patients with recalcitrant VKC, there was a 20% reduction in symptom score, and reduction in tarsal papilla size, chemosis, conjunctival swelling and injection compared to baseline [41]. In another prospective trial of 10 patients with VKC, both adults and children, the use of 0.01% topical tacrolimus drops in salt suspension for 1 month decreased signs and symptoms, although discontinuing the treatment led to a rapid recurrence of the symptoms [42]. Other small retrospective and case studies using 0.02 -- 0.1% of topical tacrolimus ointment have also shown promising efficacy in the treatment of AKC [43,44], as well as papillary conjunctivitis [45]. Ohashi et al. reported a multicentered, randomized controlled trial in Japan, which compared 0.01% tacrolimus suspension to placebo in 56 patients with severe allergic conjunctivitis (AKC and VKC) who had failed topical steroids. This study showed that after 4 weeks of treatment, there was an improvement in giant papillae (p = 0.001) and corneal involvement (p = 0.005), as well as symptoms of itching, discharge, hyperemia, lacrimation and foreign body sensation in the treatment group compared to the placebo group [46]. 5.3
Effective dose of tacrolimus Doses of tacrolimus used to treat severe allergic conjunctivitis vary from 0.02 to 0.1%, with variations in formulations ranging from aqueous solutions to skin ointment used for treatment of allergic dermatitis (applied to the eyelids). Many have demonstrated success in the treatment of refractory allergic conjunctivitis. Most of these studies were small, open-label trials or retrospective studies. Optimal doses for treatment of different forms of allergic conjunctivitis have yet to be established. 5.4
Pimecrolimus While there have been some studies in the literature examining the role of topical pimecrolimus in skin conditions, its use as an ophthalmic topical agent is extremely limited, and was mainly evaluated in animal studies [30]. 5.5
Comparison of efficacy of topical calcineurin inhibitors
5.6
Very few studies have directly compared the efficacy of one topical Cn inhibitor against another in the treatment of allergic conjunctivitis. One randomized controlled trial from Thailand compared 0.1% tacrolimus to 2% cyclosporine in 24 pediatric patients with VKC and showed improvement in signs and symptoms compared to baseline in both groups, but no statistically significant difference in the efficacy and side-effect profile between the two groups [47]. Both groups were treated with tacrolimus 0.1% for 4 weeks, following
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis
treatment with either cyclosporine or tacrolimus for 8 weeks. In an open-enrollment animal study involving canines, 1% pimecrolimus eye drop was shown to be more effective in reducing symptoms of keratoconjunctivitis sicca compared to cyclosporine ointment, but that trial was limited to symptoms of dry eyes [48]. 6.
Conclusion
There is increasing literature in the use of ophthalmic topical Cn inhibitors for treatment of severe forms of allergic conjunctivitis involving cell-mediated pathogenesis. Ophthalmic use of topical Cn inhibitors such as cyclosporine and tacrolimus has been shown to be safe with minimal systemic sideeffects, and they may prove to be effective steroid-sparing agents for use in patients with refractory allergic conjunctivitis. Smaller clinical trials generally show that topical CsA is effective in reducing signs and symptoms of allergic conjunctivitis, often reducing the need for topical steroids. Similar efficacy was seen in studies using ophthalmic tacrolimus drops, although the data are less numerous. Little is known about the effect of ophthalmic pimecrolimus drops in humans. 7.
Expert opinion
The prevalence of allergic conjunctivitis is estimated to be 20 -- 30% of the general population. In the selected population of patients with IgE-mediated allergy, 40 -- 80% has ocular symptoms. Allergic conjunctivitis is a complex condition with several subtypes and can be treated with a variety of medications, including topical antihistamines, mast cell stabilizers, NSAIDs, Cn inhibitors and corticosteroids. Topical corticosteroids are considered the mainstay of treatment for severe allergic conjunctivitis, but prolonged use has been associated with elevated intraocular pressure, glaucoma, cataract and increased susceptibility to infections. With the emergence of topical ophthalmic Cn inhibitors for a wide variety of indications ranging from dry eyes, to allergic conjunctivitis, to posttransplantation immunosuppression, there has been a rising interest in the research surrounding both safety and efficacy of topical Cn inhibitors in adults and children. Pharmacokinetic studies clearly show that Cn inhibitors are lipophilic compounds and therefore delivery vehicles such as collagen shields, a-cyclodextrin and lipid emulsion formulations must be used to achieve adequate absorption and retention
into conjunctiva, cornea and lacrimal glands. Systemic blood concentrations are not detectable with topical Cn inhibitor therapy. Unlike systemic Cn inhibitors, which have significant side-effects, ophthalmic topical Cn inhibitors, such cyclosporine and tacrolimus, have generally been shown to be safe for short-term use, with minimal systemic absorption and toxicity. Most reported adverse reactions were limited to localized discomfort and stinging sensation during instillation of the ophthalmic medication. While only few incidences of possible viral or bacterial infection involving the ocular surface have been reported, ongoing close monitoring of the patients who are on topical Cn inhibitors should be recommended. For patients with severe, refractory forms of allergic conjunctivitis such as VKC, ACK and GPC that have cell-mediated pathogenesis, topical Cn inhibitors are a promising treatment alternative for both its symptoms relief and steroid-steroid effects by controlling and maintaining quiescence of the inflammatory state. The safety profile and efficacy data for topical cyclosporine are more robust compared to that of tacrolimus and pimecrolimus, although larger, randomized controlled trials will be needed for all three agents to further elucidate the long-term safety and efficacy of these agents. Indeed, one of the weaknesses of the reported clinical trials is the short duration of therapy. Post-marketing surveillance can be helpful in detecting previously unreported adverse effects but such reports are not as robust due to the nature of the surveillance process. The ultimate goal of the treatment of allergic conjunctivitis is full control of symptoms with the lowest dose that is proven to be safe for long-term use. However, the minimal concentration of topical Cn inhibitors needed to most effectively control the signs and symptoms of allergic conjunctivitis while minimizing its side-effects has not been extensively studied and will likely vary with the different forms of allergic conjunctivitis and disease severity. With more randomized controlled trials involving larger sample size and long-term follow up to establish both efficacy and safety, ophthalmic Cn inhibitors offer exciting treatment possibilities to decrease the morbidity associated with refractory allergic conjunctivitis.
Declaration of interest The authors have no competing interests to declare and have received no funding in preparation of the manuscript.
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
547
X. C. Wan & V. Dimov
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Kari O, Saari KM. Updates in the treatment of ocular allergies. J Asthma Allergy 2010;3:149-58
2.
Sy H, Bielory L. Atopic keratoconjunctivitis. Allergy Asthma Proc 2013;34(1):33-41
3.
Bielory L. Ocular allergy treatment. Immunol Allergy Clin North Am 2008;28:189-224; vii
4.
De Smedt S, Nkhurikiye J, Fonteyne Y, et al. Vernal keratoconjunctivitis in school children in Rwanda and its association with socio-economic status: a population-based survey. Am J Trop Med Hyg 2011;85:711-17
information). Astellas Pharma US, Inc; Deerfield (IL); 2011 13.
Elidel (Pimecrolimus) cream 1 % (US prescribing information). Novartis Pharmaceuticals Corporation; East Hanover (NJ); 2001
14.
Ashcroft DM, Chen LC, Garside R, et al. Topical pimecrolimus for eczema. Cochrane Database Syst Rev 2007;(4):CD005500
15.
Gutfreund K, Bienias W, Sczewczyk A, et al. Topical calcineurin inhibitors in dermatology. Part I: properties, methods, and effectiveness of drug use. Postepy Dermatol Alergol 2013;30(3):165-9
16.
Kempen JH, Gangaputra S, Daniel E, et al. Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: acritical assessment of the evidence. Am J Ophthalmol 2008;146(6):802-12
.
administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 2005;112(10):1790-4 This paper was noteworthy in demonstrating the longer-term safety profile of topical CsA.
22.
Pleyer U, Lutz S, Jusko WJ, et al. Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. Invest Ophthalmol Vis Sci 1993;34:2737-42
23.
Bertelmann E, Pleyer U. Immunomodulatory therapy in ophthalmology -- is there a place for topical application? Ophthalmologica 2004;218:359-67
24.
Benelli U, Lepri A, Del Tacca M, et al. FK-506 delays corneal graft rejection in a model of corneal xenotransplantation. J Ocul Pharmacol Ther 1996;12:425-31
25.
Ruzicka T, Bieber T, Schopf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. European tacrolimus multicenter atopic dermatitis study group. N Engl J Med 1997;337:816-21
5.
De Smedt S, Wildner G, Kestelyn P. Vernal keratoconjunctivitis: an update. Br J Ophthalmol 2013;97(1):9-14
6.
La Rosa M, Lionetti E, Reibaldi M, et al. Allergic conjunctivitis: a comprehensive review of the literature. Ital J Pediatr 2013;39:18
17.
McCaffrey PG, Perrino BA, Soderline TR, et al. NF-ATp, a T lymphocyte DNA-binding protein that is a target for calcineurin and immunosuppressive drugs. J Biol Chem 1993;268(5):3747-52
Lallemand F, Felt-Baeyens O, Besseghir K, et al. Cyclosporine A delivery to the eye: a pharmaceutical challenge. Eur J Pharm Biopharm 2003;56(3):307-18
26.
18.
Acheampong AA, Shackleton M, Tang-Liu DD, et al. Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs. Curr Eye Res 1999;18(2):91-103
Boguniewicz M, Fiedler VC, Raimer S, et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 1998;102:637-44
27.
19.
Small DS, Acheampong A, Reis B, et al. Blood concentrations of cyclosporin A during long-term treatment with cyclosporin a ophthalmic emulsions inpatients with moderate to severe dry eye disease. J Ocul Pharmacol Ther 2002;18(5):411-18 This paper was noteworthy in studying the systemic absorption of topical CsA.
Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol 2013;131(2):295-9
28.
Yuan J, Zhai JJ, Chen JQ, et al. Preparation of 0.05% FK506 suspension eyedrops and its pharmacokinetics after topical ocular administration. J Ocul Pharmacol Ther 2009;25(4):345-50
29.
Attas-Fox L, Barkana Y, Iskhakov V, et al. Topical tacrolimus 0.03% ointment for intractable allergic conjunctivitis: an open-label pilot study. Curr Eye Res 2008;33(7):545-9
30.
Nell B, Walde J, Billich A, et al. The effect of topical pimecrolimus on keratoconjunctivitis sicca and chronic superficial keratitis in dogs: results from an exploratory study. Vet Ophthalmol 2005;8(1):39-46
31.
Ofri R, Lambrou GN, Allgoewer I, et al. Clinical evaluation of pimecrolimus eye drops for treatment of canine
7.
8.
Hunter PA, Wilhelmus KR, Rice NS, et al. Cyclosporin a applied topically to the recipient eye inhibits corneal graft rejection. Clin Exp Immunol 1981;45(1):173-7
9.
Whitcup SM, Chan CC, Luyo DA, et al. Topical cyclosporine inhibits mast cell-mediated conjunctivitis. Invest Ophthalmol Vis Sci 1996;37(13):2686-93
10.
Ebihara N, Ohashi Y, Uchio E, et al. A large prospective observational study of novel cyclosporine 0.1% aqueous ophthalmic solution in the treatment of severe allergic conjunctivitis. J Ocul Pharmacol Ther 2009;25(4):365-72
11.
12.
548
DePaulis A, Cirillo R, Ciccarelli A, et al. FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells. J Immunol 1991;146(7):2374-81 Protopic (Tacrolimus) ointment 0.03 % and ointment 0.1 % (US prescribing
.
20.
.
21.
Sall K, Stevenson OD, Mudorf TK, et al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA phase 3 study group. Ophthalmology 2000;107(4):631-9 This paper was noteworthy in establishing the efficacy and safety profile of topical CsA. Barber LD, Pflugfelder SC, Tauber J, et al. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis
32.
33.
34.
38.
Tang-Liu DD, Acheampong A. Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye. Clin Pharmacokinet 2005;44(3):247-61
Ozcan AA, Ersoz TR, Dulger E. Management of severe allergic conjunctivitis with topical cyclosporin A 0.05% eyedrops. Cornea 2007;26(9):1035-8
39.
Spadavecchia L, Fanelli P, Tesse R, et al. Efficacy of 1.25% and 1% topical cyclosporine in the treatment of severe vernal keratoconjunctivitis in childhood. Pediatr Allergy Immunol 2006;17(7):527-32
Ohashi Y, Ebihara N, Fujishima H, et al. A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis. J Ocul Pharmacol Ther 2010;26(2):165-74 Sanz-Marco E, Udaondo P, Garcı´a-Delpech S, et al. Treatment of refractory dry eye associated with graft versus host disease with 0.03% tacrolimus eyedrops. J Ocul Pharmacol Ther 2013;29(8):776-83
35.
Akpek EK, Dart JK, Watson S, et al. A randomized trial of topical cyclosporin 0.05% in topical steroid-resistant atopic keratoconjunctivitis. Ophthalmology 2004;111:476-82
36.
Daniell M, Constantinou M, Vu HT, et al. Randomised controlled trial of topical ciclosporin A in steroid dependent allergic conjunctivitis. Br J Ophthalmol 2006;90(4):461-4
37.
..
Wan KH, Chen LJ, Rong SS, et al. Topical cyclosporine in the treatment of allergic conjunctivitis: a meta-analysis. Ophthalmology 2013, doi:pii: S0161-6420(13)00329-1. 10.1016/j. ophtha.2013.03.044 This paper is particularly noteworthy in that it is a meta-analysis that examines the randomized controlled trials of topical CsA in allergic
study. Acta Ophthalmol Scand 2006;84(5):693-5
conjunctivitis. The evidence it provides is significant.
keratoconjunctivitis sicca: a comparison with cyclosporine A. Vet J 2009;179(1):70-7
40.
Hingorani M, Moodaley L, Calder VL, et al. A randomized, placebo-controlled trial of topical cyclosporin A in steroiddependent atopic keratoconjunctivitis. Ophthalmology 1998;105(9):1715-20
41.
Vichyanond P, Tantimongkolsuk C, Dumrongkigchaiporn P, et al. Vernal keratoconjunctivitis: result of a novel therapy with 0.1% topical ophthalmic FK-506 ointment. J Allergy Clin Immunol 2004;113(2):355-8
42.
Kheirkhah A, Zavareh MK, Farzbod F, et al. Topical 0.005% tacrolimus eye drop for refractory vernal keratoconjunctivitis. Eye (Lond) 2011;25:872-80
43.
Rikkers SM, Holland GN, Drayton GE, et al. Topical tacrolimus treatment of atopic eyelid disease. Am J Ophthalmol 2003;135(3):297-302
44.
Virtanen HM, Reitamo S, Kari M, Kari O. Effect of 0.03% tacrolimus ointment on conjunctival cytology in patients with severe atopic blepharoconjunctivitis: a retrospective
Expert Opin. Drug Metab. Toxicol. (2014) 10(4)
45.
Kymionis GD, Goldman D, Ide T, Yoo SH. Tacrolimus ointment 0.03% in the eye for treatment of giant papillary conjunctivitis. Cornea 2008;27(2):228-9
46.
Ohashi Y, Ebihara N, Fujishima H, et al. A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1 % in severe allergic conjunctivitis. J Ocul Pharmacol Ther 2010;26:165-74
47.
Labcharoenwongs P, Jirapongsananuruk O, Visitsunthorn N, et al. A double-masked comparison of 0.1% tacrolimus ointment and 2% cyclosporine eye drops in the treatment of vernal keratoconjunctivitis in children. Asian Pac J Allergy Immunol 2012;30:177-84
48.
Ofri R, Lambrou GN, Allgoewer I, et al. Clinical evaluation of pimecrolimus eye drops for treatment of canine keratoconjunctivitis sicca: a comparison with cyclosporine A. Vet J 2009;179(1):70-7
Affiliation
Xiao Chloe Wan1 MD & Vesselin Dimov†2 MD † Author for correspondence 1 University of Chicago, Department of Internal Medicine, 5841 South Maryland Ave MC 7082, Chicago, IL 60637, USA 2 Assistant Professor of Pediatrics and Medicine, University of Chicago, Section of Allergy, Asthma and Immunology, 5841 South Maryland Ave MC 4064, Chicago, IL 60637, USA Tel: +1 773 234 7731; E-mail: [email protected]
549
