I. Bekersky et al., Nonclinical and early clinical development of tacrolimus ointment for the treatment of atopic dermatitis, J AM ACAD D, 44(1), 2001, pp. S17-S27
Tacrolimus ointment, formulated for the treatment of atopic dermatitis, is
the first in a dass of topical immunomodulators. Its mechanism of action is
based on calcineurin inhibition, which results in suppression of antigen-s
pecific T-cell activation and inhibition of inflammatory cytokine release.
Animal and human studies have shown chat topically applied tacrolimus is mi
nimally absorbed into the systemic circulation, the fraction that is absorb
ed is extensively distributed, and tacrolimus does not accumulate in tissue
s following repeated topical application. In addition, tacrolimus ointment
is not inherently irritating, sensitizing, phototoxic, or photoallergenic w
hen applied to intact skin. Unlike some topical corticosteroids, tacrolimus
ointment does not cause a decrease in collagen synthesis or skin thickness
, nor does it produce skin abnormalities or depigmentation. In animal studi
es, repeated daily application of tacrolimus ointment up to 1 year is assoc
iated with dermal findings similar to those following vehicle application (
mild to moderate dermal irritation and microscopic findings of acanthosis,
hyperkeratosis, and superficial inflammation). In a 52-week study with Yuca
tan micropigs, no noteworthy macroscopic or microscopic changes (either der
mal or systemic) related to the application of tacrolimus ointment (0.03% t
o 0.3% concentrations) were observed. Tacrolimus ointment was shown to be s
afe and effective in phase 2 and early phase 3 studies. Significant improve
ments in atopic dermatitis were observed in the majority of patients treate
d with tacrolimus ointment. The most common adverse events associated with
its use were a transient burning sensation and pruritus at the site of appl
ication. Blood tacrolimus concentrations were below the limit of quantitati
on in most patients.