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

Mark Lebwohl, MD; Tara Gower, PhD


October 10, 2006

Low Systemic Exposure to TCIs

Pharmacokinetic data showed that when TCIs are applied to the affected skin, systemic absorption is low compared with orally administered tacrolimus.[37,38,39,40] After oral administration of a 5-mg dose of tacrolimus in healthy volunteers, the mean maximum plasma concentration was 29.7 mg/mL.[41] In transplant recipients, even higher systemic levels may be seen after oral/intravenous administration, depending on dose and the type of transplant.[41] In contrast, topical tacrolimus has a low potential for systemic absorption. In 92% of blood samples taken from 39 children with moderate-to-severe AD, the tacrolimus concentration was < 1 ng/mL.[39] In adults with moderate-to-severe AD, 76% of patients had a maximum tacrolimus blood concentration < 1 ng/mL.[40] In pharmacokinetic studies, in patients who had detectable systemic levels of tacrolimus after topical administration, the highest area under the concentration-time curve (AUC0-24 h) was 20.4 ng•hour/mL in adult patients.[38,42] This value constitutes the maximum recommended human dose (MRHD) for tacrolimus.

Likewise, low systemic absorption of topical pimecrolimus has also been observed in animal and human studies. In an animal model, small amounts of the applied dose of pimecrolimus were absorbed into the dermis, and most of this dose remained in the outermost layer of the skin, the stratum corneum. Only 0.2% of the applied molecule reached the dermis, and negligible amounts entered the systemic circulation.[37,38] In 67% of children with moderate-to-severe AD (up to 92% of body surface area affected), pimecrolimus blood levels were undetectable at < 0.5 ng/mL, and in 97%, levels were < 2.0 ng/mL.[37,38,43,44,45,46] Among patients who had detectable systemic levels of pimecrolimus after topical administration, the MRHD (AUC0-24 h) was 37.6 ng•h/mL and 22.8 ng•h/mL for pediatric and adult patients, respectively.[38]


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