Pimecrolimus (Elidel®)
Pimecrolimus
Elidel®
Classification:
Biologic Response Modifiers
Dermatological Agents
- Topical Antiinflammatory Agents
Description: Pimecrolimus (ASM 981), a derivative of ascomycin, is a topical macrolactam immunomodulator. Ascomycin was originally isolated in the early 1960s from Streptomyces hygroscopics var ascomyceticus. Pimecrolimus has similar clinical effects as tacrolimus; however, they differ in therapeutic effectiveness and formulation. Pimecrolimus has been shown to prevent atopic dermatitis flares more effectively than conventional therapy; after 6 months of treatment, 61% of patients completed treatment with pimecrolimus without a flare as compared to 35% of those treated with conventional therapy. As opposed to topical corticosteroids, no skin atrophy is noted following pimecrolimus treatment. The FDA approved pimecrolimus cream for use in children and adults with atopic dermatitis in January 2002. Data from a study released in 2005 demonstrate that pimecrolimus can maintain control of atopic dermatitis for up to 18 months without any additional treatment. On February 15, 2005, the FDA announced the addition of a Black Box warning to the professional label for Elidel® (pimecrolimus cream), instructing prescribers to use only after failure of other eczema treatments due to a possible increased cancer risk; a Medication Guide will also accompany all prescriptions for Elidel® .
Mechanism of Action: Pimecrolimus inhibits calcineurin, a calcium-dependent phosphatase, by binding with high affinity to immunophilin-12 (FKBP-12), similar to tacrolimus. Immunophilins (cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein activation. Calcineurin inhibition results in blockade of signal transduction by the cytosol component of the nuclear factor of activated T-cells (NF-AT), which results in a failure to activate NF-AT regulated genes. As a result, pimecrolimus inhibits T-cell activation by blocking transcription of early cytokines. At nanomolar concentrations, pimecrolimus inhibits interleukin (IL)-2, IL-4, IL-10, and interferon gamma synthesis. Pimecrolimus prevents the release of inflammatory cytokines and mediators (e.g., hexosaminidase, tryptase, and histamine) from mast cells in vitro after stimulation with antigen/IgE and inhibits the transcription of tumor necrosis factor (TNF) alpha. In atopic dermatitis, topical pimecrolimus acts to inhibit inflammation primarily by inhibiting T-cells.
Pharmacokinetics: Pimecrolimus is administered topically. Typically, in adults being treated for atopic dermatitis (13 - 62% body surface area (BSA) involvement), blood levels of pimecrolimus are at or below the limit of detection of the assay. If pimecrolimus is detected, the concentration is routinely < 2 ng/ml and does not accumulate with time. In vitro studies indicate that 74 - 87% of the drug would be protein bound. Following oral administration, O-demethylation metabolites are seen. Pimecrolimus appears to be metabolized in vitro by the cytochrome P450 3A family of enzymes. No evidence of skin mediated metabolism was identified in vivo or in vitro. Following a single oral dose, about 78% of the dose was recovered in the feces as metabolites; less than 1% is excreted as unchanged drug. Dosage adjustment of topical pimecrolimus in patients with hepatic or renal impairment is not necessary due to the low systemic exposure following topical administration.
References
. Bornhovd E, Burgdorf WH, Wollenberg A. Macrolactam immunomodulators for topical treatment of inflammatory skin diseases. J Am Acad Dermatol 2001;45:736 - 43.
[ Revised 1/25/2006 3:11:00 PM ]
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