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Mechanism Of Action
The mechanism of action of pimecrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T-cells. In addition, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE.
In adult subjects (n=52) being treated for atopic dermatitis [13%-62% Body Surface Area (BSA) involvement] for periods up to a year, a maximum pimecrolimus concentration of 1.4 ng/mL was observed among those subjects with detectable blood levels. In the majority of samples in adult (91%; 1,244/1,362) subjects, blood concentrations of pimecrolimus were below 0.5 ng/mL. Data on blood levels of pimecrolimus measured in pediatric subjects are described in Use in Specific Populations (8.4).
Laboratory in vitro plasma protein binding studies using equilibrium gel filtration have shown that 99.5% of pimecrolimus in plasma is bound to proteins over the pimecrolimus concentration range of 2-100 ng/mL tested. The major fraction of pimecrolimus in plasma appears to be bound to various lipoproteins. As with other topical calcineurin inhibitors, it is not known whether pimecrolimus is absorbed into cutaneous lymphatic vessels or in regional lymph nodes.
Following the administration of a single oral radiolabeled dose of pimecrolimus numerous circulating Odemethylation metabolites were seen. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A sub-family of metabolizing enzymes. No evidence of skin mediated drug metabolism was identified in vivo using the minipig or in vitro using stripped human skin.
Based on the results of the aforementioned radiolabeled study, following a single oral dose of pimecrolimus ~81% of the administered radioactivity was recovered, primarily in the feces (78.4%) as metabolites. Less than 1% of the radioactivity found in the feces was due to unchanged pimecrolimus.
Three randomized, double-blind, vehicle-controlled, multi-center, Phase 3 trials were conducted in 589 pediatric subjects ages 3 months-17 years old to evaluate ELIDEL (pimecrolimus) Cream, 1% for the treatment of mild to moderate atopic dermatitis. Two of the three trials support the use of ELIDEL Cream, 1% in subjects 2 years and older with mild to moderate atopic dermatitis [see WARNINGS AND PRECAUTIONS]. Three other trials in 1,619 pediatric and adult subjects provided additional data regarding the safety of ELIDEL Cream, 1% in the treatment of atopic dermatitis. Two of these other trials were vehicle-controlled with optional sequential use of a medium potency topical corticosteroid in pediatric subjects and one trial was an active comparator trial in adult subjects with atopic dermatitis [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Two identical 6-week, randomized, vehicle-controlled, multi-center, Phase 3 trials were conducted to evaluate ELIDEL Cream, 1% for the treatment of mild to moderate atopic dermatitis. A total of 403 pediatric subjects 2-17 years old were included in the trials. The male/female ratio was approximately 50% and 29% of the subjects were African American. At trial entry, 59% of subjects had moderate disease and the mean body surface area (BSA) affected was 26%. About 75% of subjects had atopic dermatitis affecting the face and/or neck region. In these trials, subjects applied either ELIDEL Cream, 1% or vehicle cream twice daily to 5% to 96% of their BSA for up to 6 weeks. At endpoint, based on the physician's global evaluation of clinical response, 35% of subjects treated with ELIDEL Cream, 1% were clear or almost clear of signs of atopic dermatitis compared to only 18% of vehicle-treated subjects. More ELIDEL subjects (57%) had mild or no pruritus at 6 weeks compared to vehicle subjects (34%). The improvement in pruritus occurred in conjunction with the improvement of the subjects' atopic dermatitis.
In these two 6-week trials of ELIDEL, the combined efficacy results at endpoint are presented in Table 2 as follows:
Table 2: Combined Efficacy Results at Endpoint for Two 6-week Trials of ELIDEL Cream
|Global Assessment||% Subjects|
|Clear||28 (10%)||5 (4%)|
|Clear or Almost Clear||93 (35%)||25 (18%)|
|Clear to Mild Disease||180 (67%)||55 (40%)|
In the two pediatric trials that independently support the use of ELIDEL Cream, 1% in mild to moderate atopic dermatitis, a significant treatment effect was seen by day 15. Of the key signs of atopic dermatitis, erythema, infiltration/papulation, lichenification, and excoriations were reduced at day 8 when compared to vehicle.
Figure 1 depicts the time course of improvement in the percent body surface area affected as a result of treatment with ELIDEL Cream, 1% in 2-17 year olds.
Figure 2 shows the time course of improvement in erythema as a result of treatment with ELIDEL Cream, 1% in 217 year olds.
Last reviewed on RxList: 4/11/2014
This monograph has been modified to include the generic and brand name in many instances.
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