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Elidel - Clinical Pharmacology

[pimecrolimus Cream 1%]

CLINICAL PHARMACOLOGY

Mechanism of Action/Pharmacodynamics

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.

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Pharmacokinetics

Absorption

In adult patients being treated for atopic dermatitis [13%-62% Body Surface Area (BSA) involvement] for periods up to a year, blood concentrations of pimecrolimus are routinely either at or below the limit of quantification of the assay (< 0.5 ng/mL). In those subjects with detectable blood levels they are routinely < 2 ng/mL and show no sign of drug accumulation with time. Because of the low systemic absorption of pimecrolimus following topical application the calculation of standard pharmacokinetic measures such as AUC, C max, T1/2, et cetera cannot be reliably done.

Distribution

In vitro studies of the protein binding of pimecrolimus indicate that it is 74%-87% bound to plasma proteins.

Metabolism

Following the administration of a single oral radiolabeled dose of pimecrolimus numerous circulating O-demethylation 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.

Elimination

Based on the results of the aforementioned radio labeled study, following a single oral dose of pimecrolimus ~81% of the administered radio activity 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.