L.A. Bernard, MDa, J.N. Bergman, MDa,b, L.F. Eichenfield, MDa,b
aPediatric and Adolescent Dermatology, Children’s Hospital and Health Center, San Diego, CA
bUniversity of California School of Medicine, San Diego, CA
Pimecrolimus is an immunomodulating medication that inhibits production of inflammatory cytokines in the skin and this compound was specifically developed for the treatment of inflammatory skin diseases. Phase II and III clinical trials with the topical formulation of pimecrolimus (Elidel® cream, Novartis) have shown that it is safe and effective for use in patients with atopic dermatitis (AD). The US FDA recently approved Elidel® for use in patients ≥2 years of age with mild-to-moderate atopic dermatitis (AD).
pimecrolimus, immunosuppressant, atopic dermatitis
Pimecrolimus (formerly SDZ ASM 981) is a natural macrolide product derived from the fungus Streptomyces hygroscopicus var. ascomyceticus. The topical formulation of pimecrolimus (Elidel® cream, Novartis) is one of a new class of non-steroidal topical immunosuppressant medications. When applied topically, it has cutaneous anti-inflammatory activity and appears to be minimally absorbed into the circulation. Safety and efficacy of pimecrolimus 1% cream have been established in several wellcontrolled clinical trials involving children and adults with AD. This medication was approved by the US FDA for use in adults and children (≥2 years) with mild-to-moderate AD in December 2001, and is now widely available. The product is currently undergoing regulatory review in Europe and Canada.
Mechanism of Action
The mechanism of action is closely related to that of cyclosporine, an immunosuppressant medication useful in some inflammatory skin disorders refractory to standard therapy. Oral cyclosporine is quite effective but has significant toxicities. Unfortunately, it has been found in trials to be ineffective topically.1 Efforts have been directed toward the development of new topical compounds with potent anti-inflammatory activity similar to cyclosporine, but without the systemic side effects. Topical tacrolimus and later, pimecrolimus, represent the first generation of this type of product. When applied topically, both medications selectively target inflammation in the skin without impairing systemic immune responses. In the early development phase of pimecrolimus, more than 400 ascomycin derivatives were synthesized and their characteristics explored in pre-clinical studies; SDZ ASM-981 was chosen for development because of its favorable safety profile and cutaneous efficacy.2
Pimecrolimus binds with high affinity to the T-cell receptor macrophilin 12, which leads to inhibition of calcineurin, a protein phosphatase required for activation of the T-cell. As a result, Tcell activation is inhibited, and transcription and release of proinflammatory cytokines is prevented. Additionally, pimecrolimus decreases mast cell production of pro-inflammatory cytokines (e.g., TNF-alpha) and IgE induced pro-inflammatory mediators (e.g., histamine).3 The ability of pimecrolimus to inhibit the activation of multiple cell lines and cytokines may account for its ability to effectively reduce inflammation.
In animal models, both topical and systemic pimecrolimus are highly effective against skin inflammation. However, in contrast to tacrolimus, oral pimecrolimus is a poor systemic immune suppressant,4 reducing the likelihood of systemic toxicity.
Potential interactions between pimecrolimus and other drugs have not been systematically evaluated. Systemic interactions are unlikely due to the low levels of pimecrolimus found in the blood after topical application, but cannot be ruled out based on data gathered to date. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A family of P450 enzymes. It appears to be eliminated almost completely in the bile. FDA labeling suggests that concomitant administration of known CYP3A inhibitors in patients with widespread disease be undertaken with caution.
To date, pimecrolimus has primarily been studied for use in AD, which is a chronic, highly pruritic inflammatory skin disorder and the most common chronic skin disease in childhood.5 The disease may be associated with significant morbidity and can have a significant impact on quality of life for patients and families. Additionally, research has shown that patients are often not satisfied with prescribed therapy.6
Until recently, topical treatment of AD has been limited to the use of corticosteroids. Patients who experienced side-effects from long-term use of the agents, or patients who were refractory to therapy had no other effective alternatives for topical treatment. Pimecrolimus and tacrolimus represent novel treatment options for this subset of patients.
Phase II and III trials of pimecrolimus have documented its safety and efficacy for AD treatment (summarized in Table 1). Although a few preliminary studies have been conducted using pimecrolimus to treat psoriasis and irritant hand dermatitis, its use has not yet been studied extensively for other skin conditions.7-9 Oral pimecrolimus showed efficacy and tolerability when studied for moderate-to-severe plaque psoriasis. Topical pimecrolimus has also been studied for treatment of psoriasis and has demonstrated disease improvement when used under occlusion. A study of pimecrolimus for chronic irritant hand dermatitis found that the cream safely and effectively ameliorated the signs and symptoms of the disease after 6 weeks of therapy. Based on the studies to date, it is likely that pimecrolimus will be studied for a wide variety of inflammatory skin disorders in the future.
|Design||Sample Size||Regimen||Inclusion||Primary Endpoint||Results|
|Multicenter, randomized, blinded, controlled, dose-finding Phase II11||n=260||Elidel® 0.05%, Elidel® 0.2%, Elidel® 0.6%, Elidel® 0.6%, Elidel® 1%, Vehicle, or Betamethasone valerate b.i.d. for 6 weeks||Adult patients, moderate AD||Hanifin score (a numeric score based on signs and symptoms of AD)||Elidel® 0.2%, 0.6% and 1% were more effective than vehicle, with 1% the most effective. Betamethasone valerate was more effective than all concentrations of Elidel®.|
|Multicenter, randomized, blinded, controlled Phase III (2 identical trials with pooled results)12||n=403||Elidel® 1% or Vehicle b.i.d. for 6 weeks||Patients 1-17 years of age, mild-to-moderate AD||Physician’s Global Evaluation||35% of Elidel® patients were clear or almost clear at end of study vs. 18% vehicle (p<0.05).|
|Multicenter, randomized, controlled Phase III13||n=186||Elidel® 1% or Vehicle b.i.d. for 6 weeks||Infants 3-23 months of age, mild-to-moderate AD||Physician’s Global Evaluation||By first visit, 17% of Elidel® blinded, patients were clear or almost clear vs. 9.5% in vehicle (p=0.174). By final visit, 54.5% of Elidel® patients vs. 23.8% vehicle (p<0.001) achieved this rating.|
Table 1: Review of clinical trial data.
AD Clinical Trials
The efficacy and safety of pimecrolimus in patients with AD was shown in 1998, in a small, randomized, blinded, placebo controlled trial. In 34 adult patients, pimecrolimus 1% cream proved to be superior to placebo, and no clinically significant adverse events were reported.10
Another larger, phase III, multi-center, blinded, randomized dose-finding trial also suggested efficacy and safety of pimecrolimus. This study evaluated 260 patients who were randomized to receive either 0.05%, 0.2%, 0.6%, 1% pimecrolimus, vehicle or betamethasone valerate 0.1% cream twice daily for 3 weeks. The 0.2%, 0.6% and 1% pimecrolimus creams were found to be more effective than vehicle, with 1% being the most effective. Betamethasone valerate was more effective than all concentrations of pimecrolimus. Pimecrolimusrelated adverse events included burning and a feeling of warmth in the 0.6% and 1% groups (42.9% and 48.9%, respectively, vs. 34.9% with vehicle). Based on these findings, the 1% cream was chosen for further study in phase III trials.11
Subsequently, 2 large, phase III, multi-center, randomized, controlled trials comparing pimecrolimus to vehicle were conducted in pediatric patients (aged 2-18 years) with AD. These two studies were of identical design, allowing for pooling of the results. Four hundred three patients were enrolled and both groups received treatment twice daily for 6 weeks. Efficacy was evaluated primarily by the Investigators Global Assessment (IGA), which uses a 6-point scale ranging from clear to very severe disease. The majority of patients studied had moderate disease. Treatment success was defined as achieving an IGA of 0-1 (clear to almost clear) during the study. At the first study visit (day 8), 12% of pimecrolimus patients achieved this, as compared to only 2.2% of vehicle patients (p<0.05). At the final study evaluation (day 43), 34.8% of pimecrolimus-treated patients were clear to almost clear, as opposed to only 18.4% of vehicle-treated patients (p<0.05). Pimecrolimus was also significantly more effective than vehicle at all visits for all secondary efficacy assessments studied (pruritus score and Eczema Area and Severity Index Score (EASI)). The incidence of adverse events was similar in both groups. The authors concluded that pimecrolimus 1% cream is safe and effective in children ≥2 years of age with mild-to-moderate AD.12
Another multi-center, randomized, controlled clinical trial was conducted, which compared pimecrolimus to vehicle in 186 children from 3-23 months of age. The design of this study was virtually identical to that of the two trials described previously. Patients applied medication twice daily for 6 weeks. The majority of the infants had moderate disease at study entry. By day 8, 17% of pimecrolimus-treated patients were clear or almost clear, compared with 9.5% in the placebo group (p = 0.174). By day 43 this increased to 54.5% of patients in the pimecrolimus group who were clear or almost clear and 23.8% of vehicle-treated patients (p<0.001). For all secondary efficacy parameters, pimecrolimus was significantly more effective than placebo. The incidence of adverse events was similar between the two groups. The authors concluded that pimecrolimus is safe and effective in infants aged 3-23 months with mild-to-moderate AD.13
Recently, a unique trial was conducted in pediatric patients aged 1-17 years, which suggested that pimecrolimus may be safe and effective maintenance therapy for preventing AD flares. The results also suggested a steroid-sparing effect in patients treated with pimecrolimus.14
Pharmacokinetic studies of pimecrolimus have been conducted with both adult and pediatric patients as young as 3 months of age. Measured blood concentrations of pimecrolimus were consistently low in both children and adults (99% had <2ng/ml) regardless of age, extent of body surface area (BSA) treated or duration of therapy. The majority of the readings were below the limit of quantification, even in the youngest patients. Over 12 months of treatment, there was no accumulation of the drug over time.15
Pimecrolimus cream is well tolerated when applied topically. Adverse effects have generally been limited to local irritation such as warmth, burning and pruritus. Unlike with topical corticosteroids, there has been no atrophy or adrenal axis suppression seen with Elidel®.
A significant concern exists related to local immunosuppression with topical application of tacrolimus and pimecrolimus. These agents inhibit T-cell activation and could therefore theoretically put patients at risk for conditions occurring more often in patients with T-cell suppression, namely skin cancer and viral infections. Incidence of these infections in completed trials was similar in the placebo and treated groups, but longer term data is needed to confirm that no association exists.
In summary, pimecrolimus cream is one of a new class of antiinflammatory medications that have a unique mechanism of action derived from inhibition of pro-inflammatory cytokines in the skin. It has been shown to be safe and effective in several randomized, controlled trials in patients with AD. Long term data is limited to 1 year of use and ongoing studies to assess long term safety are appropriate. Based on the information gathered to date, it is likely that in the future, pimecrolimus will be used extensively for AD and a variety of other inflammatory skin conditions.
- Atakan N, Erdem C. The efficacy, tolerability and safety of a new oral formulation of Sandimmun-Sandimmun Neoral in severe refractory atopic dermatitis. J Eur Acad Dermatol Venereol 11(3):240-6 (1998 Nov).
- Stuetz A, Grassberger M, Meingassner J. Pimecrolimus (Elidel, SDZ ASM 981) ñ preclinical pharmacologic profile and skin selectivity. Semin Cutan Med Surg 20(4):233-41 (2001 Dec).
- Neckermann G, Bavandi A, Meingassner JG. Atopic dermatitis-like symptoms in hypomagnesaemic hairless rats are prevented and inhibited by systemic or topical SDZ ASM 981. Br J Dermatol 142(4):669-79 (2000 Apr).
- Grassberger M, Baumruker T, Enz A, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol 141(2):264-73 (1999 Aug).
- Laughter D, Istvan J, Tofte S, Hanifin J. The prevalence of atopic dermatitis in Oregon schoolchildren. Jl Am Acad Dermatol 43(4):649-55 (2000 Oct).
- Paller A, McAllister R, Doyle J, et al. Atopic dermatitis in pediatric patients: perceptions of physicians and parents. At: American Academy of Dermatology Annual Meeting, (2000 Mar) San Francisco, CA.
- Greig G, Burtin P, Wolff K, et al. Oral SDZ ASM 981: Clinical safety, tolerability, and efficacy in patients with moderate to severe chronic plaque psoriasis. At: American Academy of Dermatology Annual Meeting, (2001, Mar) Washington D.C.
- Mrowietz U, Graber M, Brautigam M, et al. The novel ascomycin derivative SDZ ASM 981 is effective for psoriasis when used topically under occlusion. Br J Dermatol 139(6):992-6 (1998 Dec).
- Cherill R, Tofte S, MacNaul R, et al. 1% SDZ ASM 981 cream effective in treatment of chronic irritant hand dermatitis: a 6 week, randomized, doubleblind, vehicle-controlled, single-center study. J Eur Acad Dermatol Venereol 14(suppl 1):128 (2000).
- Van Leent E, Graber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol 134(7):805-9 (1998 Jul).
- Luger T, Van Leent E, Graber M, et al. SDZ ASM 981: An emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 144(4):788-94 (2001 Apr).
- Eichenfield L, Lucky A, Boguniewicz M, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. Jl Am Acad Dermatol 46(4):495-504 (2002 Apr).
- Papp K, Ho V, Halbert A, et al. Pimecrolimus (Elidel®, SDZ ASM 981) cream 1% is effective and safe in infants aged 3-23 months with atopic dermatitis. At: World Congress of Pediatric Dermatology, (2001 May) Cancun, Mexico.
- De Prost Y, Wahn U, Bos J et al. Pimecrolimus cream reduces the number of flares and the need for topical corticosteroids in children with atopic dermatitis: a 12 month, double-blind, controlled study. At: American Academy of Dermatology Annual Meeting, (2002 Feb), New Orleans, LA.
- Wahn U, Praiser D, Gottlieb A, et al. Low blood concentrations of SDZ ASM 981 in infants with extensive atopic dermatitis treated with cream 1%. At: American Academy of Dermatology Annual Meeting, (2001 Mar), Washington D.C.