Pharmacology: 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 eg, 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: Clinical data have shown that tacrolimus concentrations in systemic circulation after topical administration are low and, when measurable, transient.
Absorption: Data from healthy human subjects indicate that 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 (0.03-0.3%) had blood concentrations <1 ng/mL. When observed, blood concentrations exceeding 1 ng/mL were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and 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 (ie, AUC) of tacrolimus from Protopic 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 1 year) with tacrolimus ointment.
Distribution: As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) to plasma proteins is considered not to be clinically relevant.
Metabolism: Metabolism of tacrolimus by human skin was detectable. Systemically available tacrolimus is extensively metabolized in the liver via CYP3A4.
Elimination: When administered IV, tacrolimus has been shown to have a low clearance rate. The average total body clearance is approximately 2.25 L/hr. 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 hrs for adults and 65 hrs for children.
Toxicology: Preclinical Safety Data: In chronic toxicity studies in rats up to 26 weeks, rabbits up to 28 days, or in micropigs up to 52 weeks, repeated topical administration of tacrolimus ointment or the ointment vehicle was associated with slight dermal changes eg, erythema, edema and papules. Tacrolimus ointment (0.03-3%) did not induce contact hypersensitivity or photosensitization in guinea pigs or cutaneous phototoxicity in albino hairless mice.
There was no evidence of mutagenic potential.
In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumors were observed. In the same study an increased incidence of lymphoma was detected in association with high systemic exposure.
In a photocarcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation exposure (40 weeks of treatment followed by 12 weeks of observation) with 0.1% tacrolimus ointment.
Reproductive toxicology studies were not performed with topical tacrolimus. In studies of oral tacrolimus no impairment of fertility was seen in male and female rats.