title: Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated.
abstract: The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release inhibitor that so far has not been administered systemically to humans. In this phase I/II randomized double-blind, placebo-controlled, multiple rising dose proof of concept study psoriasis patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation but no changes in gene expression linked to drug-related side-effects. A steady state of pimecrolimus was reached after 5-10 d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per ml, respectively, at steady state at the highest dose. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%, respectively. Histopatho logically and immunopathologically there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. We conclude that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated and this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases.
authors.affiliation: Department of Dermatology, Division of General Dermatology, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Klemens
authors.initials: K
authors.lastname: Rappersberger
authors.forename: Michael
authors.initials: M
authors.lastname: Komar
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Ebelin
authors.forename: Graham
authors.initials: G
authors.lastname: Scott
authors.forename: Pascale
authors.initials: P
authors.lastname: Burtin
authors.forename: Gerard
authors.initials: G
authors.lastname: Greig
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kehren
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.forename: Andre
authors.initials: A
authors.lastname: Cordier
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Holter
authors.forename: Leo
authors.initials: L
authors.lastname: Richter
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
authors.forename: Anton
authors.initials: A
authors.lastname: Stuetz
authors.forename: Klaus
authors.initials: K
authors.lastname: Wolff
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D016559:Tacrolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C117268:pimecrolimus; D016559:Tacrolimus