A Safety Assessment of Topical Calcineurin Inhibitors in the Treatment of Atopic Dermatitis

Mark Lebwohl, MD; Tara Gower, PhD

Disclosures

October 10, 2006

Toxicology of Calcineurin Inhibitors in Animal Models

In a 2-year dermal carcinogenicity study in mice that were treated with tacrolimus ointment 0.1% and 0.03%, the incidence of skin malignancies was minimal and topical application was not associated with skin-tumor formation.[12] In that same study, pleomorphic and undifferentiated lymphomas were noted in mice that were treated with tacrolimus ointment 0.1%, at 26 times the MRHD, whereas no lymphomas were noted in mice that were treated with tacrolimus ointment 0.03%, which corresponds to 10 times the MRHD (Figure 5).[38,42]

Figure 5.

Mean area under the time-concentration curves of tacrolimus and pimecrolimus in animal and human studies. International Conference on Harmonisation (ICH) Guidelines: Maximum recommended human dose (MRHD) (highest mean exposure) of 25 times or greater represents an adequate safety margin. In murine toxicology studies, no malignancies were observed with exposure to tacrolimus ointment 0.03% at 10 times the MRHD; at 26 times the MRHD, lymphoma was seen with tacrolimus ointment 0.1%.[12,37,57] NOAEL = no observed adverse-effect level; LOAEL = lowest observed adverse-effect level.

Carcinogenicity studies of pimecrolimus in mice have also failed to demonstrate an increased risk for malignancy. In a mouse dermal carcinogenicity study with pimecrolimus in an ethanolic solution, no malignancies were seen in mice that were exposed long term (2 years) at 27 times and 45 times the highest AUC that has ever been observed for pediatric and adult patients, respectively (Figure 6).[37,38,42] Lymphomas have been noted in mice exposed at 77 times the MRHD for pimecrolimus cream 1%, when dissolved in ethanolic solution to enhance penetration (Figure 6).

Figure 6.

Mean area under the time-concentration curves (AUCs) of tacrolimus and pimecrolimus in animal and human studies. International Conference on Harmonisation (ICH) Guidelines: Maximum recommended human dose (MRHD) (highest mean exposure) of 25 times or greater represents an adequate safety margin. No malignancies were observed in mice that were treated for 2 years with exposure to pimecrolimus at 45 times the MRHD in adult patients; at 77 times the MRHD, lymphoma was seen.[12,37,57] NOAEL = no observed adverse-effect level; LOAEL = lowest observed adverse-effect level.

Additionally, toxicology studies of oral tacrolimus and pimecrolimus have been conducted in cynomolgus monkeys. In a tacrolimus study, one of the 4 cynomolgus monkeys that was treated with oral doses of 10 mg/kg/day of tacrolimus for 90 days developed malignant lymphoma.[58] In contrast, none of the 4 monkeys receiving 1 mg/kg/day of oral tacrolimus had evidence of lymphoma or any other biochemical or histopathologic changes.[58] Similarly, in pimecrolimus studies, 1 of 8 animals treated orally with 15 mg/kg/day (31 times the MRHD) for 39 weeks developed lymphoproliferative disease.[38] However, a partial recovery from lymphoproliferative disease was noted upon cessation of pimecrolimus administration.

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