Tacrolimus Ointment (Protopic®) for Atopic Dermatitis

J. C. Pascual, MD¹, A. B. Fleischer, Jr., MD²

¹Department of Dermatology, Hospital General de Alicantem, Alicante, Spain
²Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

ABSTRACT

Tacrolimus ointment (Protopic^®, Fujisawa) is an effective agent in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in decreased T-cell activation and inflammatory cytokine release. Tacrolimus ointment is safe and effective for short- and long-term treatment of atopic dermatitis (AD) in pediatric and adult patients. The most common adverse events associated with its use are a transient burning sensation and pruritus at the site of application. Unlike topical corticosteroid agents, tacrolimus ointment does not cause a reduction in collagen synthesis or skin thickness. Because tacrolimus ointment does not cause skin atrophy, it may be safely used for months or years on all skin areas, including the face and intertriginous areas.

Key Words: tacrolimus, immunomodulator, atopic dermatitis, eczema, calcineurin, skin

Background

Atopic dermatitis (AD) is a common chronic inflammatory skin condition affecting up to 20% of school children.^1,2 Pruritus is the dominant symptom in AD and may lead to damaging excoriations, erosions, and lichenification. Other important features include a chronic recurring course, a family or personal history of atopy, and a characteristic distribution of lesions. The burden of AD on health-related quality of life can be profound.³

Preventing and modulating trigger factors should be a lifelong goal of patients. A major factor that exacerbates AD is xerosis (dry skin). Caused in part by poor bathing and moisturizing practices, this factor may be minimized by patient counseling. Despite the lack of quality, randomized controlled trials demonstrating their use, moisturizers are critical in the management of AD and they should be used regularly by all patients.⁴

Topical corticosteroid agents have been the mainstay for AD for the last 40 years, and their effectiveness is supported by randomized controlled trials.⁵ In general, topical corticosteroids should only be used intermittently to control exacerbations.

A new class of topical immunomodulatory macrolides is available for the treatment of AD and other inflammatory dermatoses. There are two drugs currently on the market, tacrolimus ointment (Protopic^®, Fujisawa) and pimecrolimus cream (Elidel^®, Novartis). Both molecules are active due to calcineurin inhibition, which results in suppression of antigen-specific T-cell activation and inhibition of inflammatory cytokine release (see Table 1).

Table 1: Topical treatments for atopic dermatitis

Development and Mechanism of Action of Tacrolimus

Tacrolimus is a 23-member macrolide produced by Streptomyces tsukubaensis. The name tacrolimus is derived by taking the “t” for Mount Tsukuba (where the organism was discovered), “acrol” for macrolide and “imus” for immunosuppressant. It is also referred to as FK506, its research compound designation.

There is a series of complex immunodysregulatory responses in some patients who have AD. The T-lymphocytes are activated, which in turn release cytokines, and interact with a broad range of other cell types in the dermis and epidermis. Tacrolimus acts directly on the T-lymphocytes, especially CD4+ cells, by binding to the FK-binding protein (FKBP). This tacrolimus-FKBP complex then binds to and competitively inhibits calcineurin, a phosphatase that is active only when bound to calcium and calmodulin. This binding phenomenon inhibits the ability of calcineurin to dephosphorylate the transcription factor, NFAT (nuclear factor of activated T-cells). It is this transcription factor that activates the promoter region of the gene for various inflammatory cytokines that participate in the early immune response and are postulated to play a role in AD pathogenesis.⁶

Tacrolimus inhibits the release of mast cell and basophil preformed mediators, downregulates IL-8 receptor expression, decreases intercellular adhesion molecule-1 and E-selectin lesional blood vessel expression, and downregulates FceRI on Langerhans cells. This broad range of the inflammatory inhibition mechanism may reduce antigen recognition and downregulate the entire inflammatory cascade leading to clinical disease.

Pharmacokinetics of Tacrolimus

Results from several pharmacokinetic studies of both pediatric and adult patients with AD demonstrated that tacrolimus was minimally absorbed into the systemic circulation.^7-10 Despite the relatively high molecular weight of 822Da, tacrolimus has relatively robust cutaneous penetration.⁶ The concentrations of tacrolimus in the skin, compared to corresponding blood concentrations, were 800-1,800 times higher in patients with mostly severe AD.¹⁰  As patients’ barrier function improves, the percutaneous absorption of tacrolimus decreases, which is similar to corticosteroid treatment. The minimal absorption and self-regulatory property of tacrolimus indicates that tacrolimus has minimal long-term systemic safety issues.¹¹  Blood tacrolimus concentrations after topical application of tacrolimus ointment were measured at various times during several studies in adults and/or pediatric patients with AD. Tacrolimus concentrations were below the limit of quantification (<0.5ng/ml) in 75%–90% of blood samples.^6,12-14 Quantifiable tacrolimus blood concentrations were isolated events and were not observed in any individual patient for a prolonged period. Furthermore, tacrolimus does not seem to accumulate, either in the skin or blood, following repeated applications.⁷

Efficacy of Tacrolimus Ointment in Atopic Dermatitis

In the first definitive, randomized, double-blind, multicenter study, 0.03%, 0.1%, and 0.3% tacrolimus ointment were compared with vehicle alone in patients with moderate-to-severe AD. After just 3 days of treatment, statistically significant changes occurred in all three treatment groups when compared with the vehicle group, indicating that clinical response is as rapid as that observed with topical corticosteroid agents.¹⁵

Hanifin, et al.¹⁶ found tacrolimus 0.03% and 0.1% to be more effective than the vehicle in treating moderate-to-severe AD. In this report of 632 adults who used tacrolimus twice daily for up to 12 weeks, a 90% or greater improvement from baseline in AD was observed in 37% of patients in the tacrolimus 0.1% group, 27% in the tacrolimus 0.03% group, and 7% of patients applying the vehicle.

In order to assess the impact of tacrolimus treatment on patients’ quality of life, Drake, et al.³ conducted a study designated to measure subjectively the effects of topical tacrolimus in adults, children, and toddlers with AD. Treatment with tacrolimus ointment 0.03% and 0.1% was observed to significantly improve their quality of life.

To evaluate the long-term efficacy in the pediatric population, Kang, et al.¹⁷ treated 225 children with AD, aged 2-15 years, with tacrolimus ointment 0.1% for up to 12 months. Substantial improvement was observed during the first week and maintained during the course of the study. Subsequent studies conducted over several years suggest that safety and efficacy continues unabated.^18,19 These results suggest that tachyphylaxis to this agent does not occur over periods of several years.

Tacrolimus seems to be equivalent to moderate-to-potent topical corticosteroids. Reitamo, et al.²⁰ compared tacrolimus ointment (0.1% and 0.03%) with hydrocortisone butyrate ointment, a medium-to-potent topical corticosteroid, for up to 3 weeks, in a multicenter, randomized, double-blind, parallel-group study. The study of 570 adults with moderate-to-severe AD found that 0.1% tacrolimus ointment was at least as effective as 0.1% hydrocortisone butyrate ointment. In a similar study over a longer duration (6 months) in 972 adults with moderate-to-severe AD, significantly greater improvement occurred in the 0.1% tacrolimus ointment group, compared with the 0.1% hydrocortisone butyrate group (p<0.001).²¹

Comparison of Tacrolimus with Pimecrolimus

Topical tacrolimus and pimecrolimus have not been directly compared in a published, controlled clinical trial. Nevertheless, we may draw inferences from the medical literature. A double-blind, randomized, parallel-group, multicenter study compared pimecrolimus cream with betamethasone valerate, a mid-potency topical corticosteroid agent. In this trial, betamethasone valerate was more effective than pimecrolimus cream 1%.²² Because topical tacrolimus is at least as effective as a mid-to-high potency corticosteroid agent, and tacrolimus demonstrates a 3-fold greater binding affinity to the FKBP compared with pimecrolimus, pimecrolimus can be expected to be substantially less effective.²³ This is further corroborated by the finding that tacrolimus ointment (0.1% and 0.03%) is approved for moderate-to-severe AD, whereas pimecrolimus cream in over 30 times the drug concentration (1%) is approved for mild-to-moderate AD.

In a recent multicenter, randomized, investigator-blinded, comparative study performed by one of the authors (ABF) and presented at the 2003 European Academy of Dermatology and Venereology Meeting, tacrolimus ointment 0.1% was substantially more effective than pimecrolimus 1% cream. This study of children, aged 2–16 with moderate-to-severe atopic dermatitis followed subjects prospectively for 6 weeks. Of 193 evaluable total subjects, nearly twice as many achieved clearance or near clearance with tacrolimus than with pimecrolimus (38% vs. 20%, p=0.006). There were no differences in side-effect profile including burning, stinging, and itching. These data confirm the expected efficacy differences and confirm the relative safety of both as being indistinguishable.

Although supporting the use of topical tacrolimus by dermatology specialists, the National Prescribing Centre in Britain recently recommended against the general use of pimecrolimus, given its limited efficacy.⁴ Despite these recommendations, the authors of this review, as dermatologists, do prescribe pimecrolimus. Pimecrolimus is especially useful for adult patients to use in the morning on the face, to avoid the shininess of an ointment. When given a choice between a more effective ointment and a less effective cream, most but not all patients will choose the ointment.

Combinations with Corticosteroid Agents

A recent study concluded that concomitant therapy with clocortolone pivalate cream 0.1% and tacrolimus ointment 0.1% in AD may minimize the potential adverse effects of both treatments taken alone and may potentially improve overall response.²⁴ Physicians in practice often combine tacrolimus with corticosteroids, vitamin D analogs, and other agents to obtain synergy. The development of synergistic regimens remains in its infancy, but will continue to be expanded.

Disease Flare Treatment

Although tacrolimus is a safe and effective long-term treatment for atopic dermatitis, disease flares can and do occur. Disease severity fluctuates over time, and when flares occur that tacrolimus therapy will not suppress, patients benefit from combination treatment using corticosteroid agents, antimicrobial therapy, and appropriate barrier recovery approaches (e.g., moisturizers). The advantage of tacrolimus is that, like pimecrolimus, this agent can reduce the number of days of patient exposure to topical corticosteroid agents.

Safety and Adverse Events of Tacrolimus Ointment in Atopic Dermatitis

Several studies have been carried out to determine the safety of tacrolimus ointment in the short- and long-term.^12,17 These studies have shown that tacrolimus ointment 0.1% and 0.03% is a safe drug in adults and children. The most common adverse events were the transient sensation of skin burning and pruritus in the place of application. The prevalence of these mild application-site adverse events was highest during the first few days of treatment and declined as the skin healed. No cases of skin atrophy were reported.

Theoretically, a topical immunomodulatory agent, such as tacrolimus, has the potential to increase the risk of cutaneous infections by altering local cutaneous immune response. In controlled trials, treatment with tacrolimus does not increase the risk of bacterial, fungal, or viral infections.²⁵ One explanation is that the better disease control obtained improves the epidermal barrier function, resulting in a decreased risk of local infection.

Theoretically, there is a possibility that topical immunomodulators could increase the long-term risk of cutaneous oncogenesis. Patients on daily systemic cyclosporine and tacrolimus for prevention of allograft rejection do bear substantially increased risk of developing skin cancers. Patients using topical immunomodulators such as tacrolimus and pimecrolimus have certain advantages over the transplant population, especially inasmuch as they are likely to utilize treatment in different skin areas at different times, and daily treatment over a period of years with either agent is reserved for the most severe patient population. Nevertheless, it is prudent that all patients, especially those using topical immunomodulators, carefully protect themselves from solar exposure using appropriate protective garments and sunscreens.

Tacrolimus Ointment for Atopic Dermatitis and Other Inflammatory Dermatoses

Tacrolimus ointment is available in two concentrations (0.1% and 0.03%), both of which are licensed for treatment of moderate-to-severe AD. The lower concentration is licensed for children aged 2 years, but in both adults and children this lower concentration is less effective and no safer than the higher concentration. It is becoming increasingly clear that these topical immunomodulatory agents are also safe to use in children less than 2 years of age,²⁶ but further information will be needed before establishing the safety and efficacy profiles of these agents in this age group.

Additionally, cases have been reported showing the value of topical tacrolimus for other inflammatory dermatoses, including alopecia areata, hand eczema, vitiligo, lichen sclerosis, chronic actinic dermatitis, chronic contact dermatitis, lichen striatus, eyelid dermatitis, lupus erythematosus, seborrheic dermatitis, facial and intertriginous psoriasis, and other conditions. All of these chronic conditions, like atopic dermatitis, benefit from safe, long-term management approaches that minimize lifetime exposure to corticosteroid agents.

Conclusion

Tacrolimus ointment is the first and most potent in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in decreased T-cell activation and inflammatory cytokine release. It has been shown to be safe and effective in adults and children with AD in short- and long-term treatments. Tacrolimus ointment does not cause skin atrophy and can be safely used over the long term on any location. Although this agent has primarily been tested as monotherapy for a wide variety of inflammatory conditions, using it in combination with corticosteroids and vitamin D analogs will likely be proven useful. Topical tacrolimus occupies a unique place in the treatment of AD and other inflammatory dermatoses.

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