Pharmacotherapeutic group: Other dermatologicals. ATC code: D11AH01.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known.
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium-dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ.
In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory mediators from skin mast cells, basophils and eosinophils.
In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis in humans.
Pharmacokinetics: Tacrolimus concentrations in systemic circulation after topical administration are low and, when measurable, transient.
Absorption: In healthy humans, there is little or no systemic exposure to tacrolimus following single or repeated topical application of tacrolimus ointment.
Most atopic dermatitis patients (adults and children) treated with single or repeated application of tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated with tacrolimus ointment (0.03%) had blood concentrations < 1.0 ng/ml. When observed, blood concentrations exceeding 1.0 ng/ml were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus from tacrolimus ointment is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic effects can be observed is not known.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for prolonged periods (up to one year) with tacrolimus ointment.
Distribution: As systemic exposure have been seen low with tacrolimus ointment, the high binding of tacrolimus (> 98.8%) to plasma proteins is considered not to be clinically relevant.
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skin with minimal diffusion into the systemic circulation.
Metabolism: Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is extensively metabolised in the liver via CYP3A4.
Elimination: When administered intravenously, tacrolimus has been shown to have a low clearance rate. The average total body clearance have been seen approximately 2.25 l/h. The hepatic clearance of systemically available tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co-treated with drugs that are potent inhibitors of CYP3A4.
Following repeated topical application of the ointment the average half-life of tacrolimus was estimated to be 75 hours for adults and 65 hours for children.
Paediatric population: The pharmacokinetics of tacrolimus after topical application are similar to those reported in adults, with minimal systemic exposure and no evidence of accumulation.