Nonclinical and early clinical development of tacrolimus ointment for the treatment of atopic dermatitis.

Tacrolimus ointment, formulated for the treatment of atopic dermatitis, is the first in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition, which results in suppression of antigen-specific T-cell activation and inhibition of inflammatory cytokine release. Animal and human studies have shown that topically applied tacrolimus is minimally absorbed into the systemic circulation, the fraction that is absorbed is extensively distributed, and tacrolimus does not accumulate in tissues following repeated topical application. In addition, tacrolimus ointment is not inherently irritating, sensitizing, phototoxic, or photoallergenic when 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 studies, repeated daily application of tacrolimus ointment up to 1 year is associated 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 Yucatan micropigs, no noteworthy macroscopic or microscopic changes (either dermal or systemic) related to the application of tacrolimus ointment (0.03% to 0.3% concentrations) were observed. Tacrolimus ointment was shown to be safe and effective in phase 2 and early phase 3 studies. Significant improvements in atopic dermatitis were observed in the majority of patients treated with tacrolimus ointment. The most common adverse events associated with its use were a transient burning sensation and pruritus at the site of application. Blood tacrolimus concentrations were below the limit of quantitation in most patients.

Tacrolimus vs. cyclosporine immunosuppression: results in advanced-stage disease compared with historical controls treated exclusively with cyclosporine.

A phase HI comparative trial of tacrolimus- vs. cyclosporine-based graft-vs.-host disease (GVHD) prophylaxis for human leukocyte antigen (HLA)-identical sibling bone marrow transplantation showed less GVHD but poorer survival in the tacrolimus arm. To test the comparability of the two treatment arms with respect to baseline survival prognosis, a matched control study using exclusively cyclosporine-treated patients from the International Bone Marrow Transplant Registry (IBMTR) database was performed. Controls were matched (2:1) based on age (within 5 years), disease, and pretransplant disease status. Two-year survival for tacrolimus-treated clinical trial patients was similar to that of their cyclosporine-treated matched controls (27 and 24%, respectively), and 2-year survival of the cyclosporine-treated clinical trial patients was similar to that of their cyclosporine-treated matched IBMTR controls (42 and 45%, respectively). Consistent with the clinical trial results, the cyclosporine-treated IBMTR controls matched to the tacrolimus group had significantly poorer 2-year survival than the cyclosporine-treated IBMTR controls matched to the cyclosporine group (24 and 45%, respectively; p < 0.01). No significant difference was seen in GVHD between the cyclosporine-treated clinical trial patients and their matched controls; however, the tacrolimus-treated clinical trial patients had significantly less GVHD than their cyclosporine-treated IBMTR controls (p < 0.01). These results support the hypothesis that the survival difference in the phase III trial resulted from an imbalance in the underlying risk factors for death in the two groups rather than from the randomized immunosuppressive regimen.