Protopic Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: The exact mechanism of action of topically applied tacrolimus in atopic dermatitis is unknown. Tacrolimus has been shown to inhibit calcineurin and subsequent calcium dependent signaling for transcription and synthesis of cytokines such as interleukins (IL-2, IL-3, IL-4, IL-5, IFN-gamma, TNF-alpha, and GM-CSF) that are involved in early T-cell activation. Clinical significance of these actions in atopic dermatitis is not known.
Results from clinical studies in patients: [Treatment]: Five large, multicenter, randomized, double-blind, parallel group Phase III comparative studies were conducted in patients with atopic dermatitis: 3 adult studies (1 in Europe and 2 in the U.S.) and 2 pediatric studies (1 in Europe and 1 in the U.S.).
European studies: The primary efficacy endpoint for the European reference therapy controlled studies was the mEASI AUC (modified Eczema and Severity Index area under the time-curve) as a percent of baseline and averaged over the treatment period. These studies show that the efficacy of 0.1% tacrolimus ointment is similar to that of the potent topical corticosteroid 0.1% hydrocortisone butyrate ointment and greater than that of 0.03% tacrolimus ointment, and that 0.03% tacrolimus ointment is more effective than 1% hydrocortisone acetate.
U.S. Studies: The 3 U.S. trials were vehicle-controlled, and the primary efficacy endpoint was the rate of treatment success (≥ 90% improvement) at the end of the 12-week treatment period. All 3 U.S. studies showed both 0.03% and 0.1% tacrolimus ointment to be more effective than vehicle (P ≤ 0.001).
Findings from the 2 reference therapy controlled studies and the 3 vehicle controlled studies are consistent and indicate that both 0.03% and 0.1% tacrolimus ointment are effective in the treatment of atopic dermatitis in adult and pediatric patients.
Pharmacokinetics: Absorption: Most atopic dermatitis patients (adults and children) treated with single or repeated application of tacrolimus ointment (0.03 – 0.1%) had blood concentrations less than 2 ng/mL.
Toxicology: Pre-clinical safety data: Mutagenicity: In vitro and in vivo tests did not indicate a genotoxic potential of tacrolimus.
Carcinogenicity: In a 24-month dermal carcinogenicity study of tacrolimus ointment at up to 0.1%, no skin tumors were observed, however, an increased incidence of lymphoma was detected in association with high systemic exposure.
In a 52-week photocarcinogenicity study, the median time to onset of skin tumor formation was decreased in albino hairless mice following chronic topical dosing with tacrolimus ointment at ≥ 0.1 % tacrolimus concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation).
Reproduction toxicity: Reproductive toxicology studies were not performed with topical tacrolimus. In the studies of oral tacrolimus, embryo/fetal toxicity was observed in rats and rabbits, but only at doses that caused significant toxicity in maternal animals.