Pimecrolimus: skin disposition after topical administration in minipigs in vivo and in human skin in vitro.
The dermal disposition of pimecrolimus, a non-steroid, anti-inflammatory calcineurin inhibitor used for the treatment of atopic dermatitis, was evaluated in minipigs in vivo and in human skin in vitro using tritium-radiolabeled compound, and in dermal toxicokinetic investigations in minipigs using unlabeled compound. Following topical application of pimecrolimus 1% market form (MF) cream to minipig skin, approximately 2% of the dose penetrated into the stratum corneum and part of it into deeper skin layers. The remainder of the dose was recovered non-absorbed on the skin surface. The total systemic absorption was <or=0.8% of dose. Highest pimecrolimus blood concentrations (0.44 ng/mL) were reached between 2 and 6h post-end of topical application. Most of the absorbed drug was excreted as metabolites with feces. In human skin treated in vitro with pimecrolimus 1% MF cream for 24h, >or=94% of dose remained non-absorbed, 3.1% was found in the epidermis (including stratum corneum) and 2.9% in the dermis. There was no indication of metabolism of pimecrolimus in human skin in vitro or minipig skin in vivo. No drug accumulation was observed in minipig skin after up to 13 weeks of once daily topical application of 0.1% or 0.3% pimecrolimus cream.
Gschwind
Hans-Peter
HP
Novartis Pharma AG, Exploratory Development/DMPK, WKL-135.2.25, CH-4002 Basel, Switzerland. hans-peter.gschwind@novartis.com
Waldmeier
Felix
F
Zollinger
Markus
M
Schweitzer
Alain
A
Grassberger
Maximilian
M
D000279:Administration, Cutaneous; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D065095:Calcineurin Inhibitors; D002845:Chromatography / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D015394:Molecular Structure; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D013552:Swine; D013556:Swine, Miniature; D016559:Tacrolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014316:Tritium
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065095:Calcineurin Inhibitors; D014316:Tritium; C117268:pimecrolimus; D016559:Tacrolimus