Letters to Dermatology 260 Dermatology 2006;212:260–261 DOI: 10.1159/000091256 Significantly Elevated Systemic Levels after Occlusive Application of Topical Tacrolimus in Atopic Dermatitis Mirjam Beyeler, Peter Schmid-Grendelmeier, Jürg Hafner Department of Dermatology, University Hospital Zürich, Zürich, Switzerland After a single application of tacrolimus ointment maximal blood levels are reached within 4–6 h whereas during continuous treatment maximal values are reached after 3–4 days. The maxi- mum reported level was 20 ng/ml in 2 adult patients with atopic dermatitis receiving 10 and 20 g of ointment, respectively [3]. In one case of Netherton syndrome, 15 g of tacrolimus ointment 0.1% per day led to a maximum blood level of 37.2 ng/ml [4]. Tacrolimus is an immunosuppressive agent with a lower mo- lecular weight than cyclosporin A and therefore suitable for percu- taneous resorption and topical immune suppression. It is a macro- lide antibiotic and was approved by the US Food and Drug Admin- istration (FDA) in 1994 for allogeneic liver transplantation [5]. Meanwhile, the indications have been extended, especially due to the low toxicity and good tolerability. The pharmacokinetic profile of tacrolimus is variable, probably to some extent because the ma- jor route of metabolism is via intestinal and hepatic cytochrome P450 3A4. The therapeutic range of tacrolimus has not been clear- ly defined, but most authors consider it to be within the range of 5–20  g/l in whole blood [6]. Generally, high tacrolimus concentra- tions are likely to be required in the initial posttransplant period, but target concentrations can then be reduced over time. Rubins et al. [7] investigated pharmacokinetic parameters of topical tacrolimus. There was a trend for systemic exposure to in- crease proportionally as the size of the treatment area increased, but exposure was still substantially lower than for transplant pa- tients. The patients with more severe atopic dermatitis and a high- er number of open lesions tended to have an initially higher absorp- tion of tacrolimus. As the skin lesions healed, the systemic exposure to tacrolimus decreased. For a 60-kg patient, an oral loading dose of 20 mg tacrolimus is given to reach systemic levels between 10 and 20  g/l. The level measured in our patient suggests that systemic absorption of topi- cal tacrolimus may reach levels corresponding to almost 100% to those of oral doses. This fact may be promoted by ‘Unna’s paste boots’. In conclusion, the increased systemic absorption in our case has to be attributed to three major factors: (1) a severely damaged skin barrier function favoring systemic absorption, (2) application of topical tacrolimus to a large surface of lesional skin, and (3) occlu- sive application under ‘Unna’s paste boots’ (zinc bandages). Since this mode of application is in contrast to the manufacturer’s recom- mendations (Fujisawa Healthcare), we monitored systemic drug levels, which were found to be within the therapeutic range. How- ever, for effective immunosuppression long-term immunosuppres- sive levels are required whereas in topical treatment blood levels decrease with repair of the skin barrier. The impressive remission, hence, had to be attributed to both local and systemic immunosuppression. We stopped topical tacro- limus and switched to a moisturizung local treatment combined with UV therapy (UVA and B). The skin condition remained sta- ble. Hence, large surface treatment with topical tacrolimus under occlusion can lead to relevant systemic blood levels that may induce systemic immunosuppression. Key Words Topical tacrolimus  Occlusive application  Blood level A 50-year-old female was referred to our department in June 2004 for the treatment of erythrodermic atopic dermatitis. The di- agnosis of atopic dermatitis was made in 1998 and since October 2003, the patient has been suffering from a steady deterioration of her eczema. Treatment with local or systemic steroids brought only short relief. Rapid progression to an erythrodermic stage made in- patient treatment necessary. Because of the extent of the skin lesions, we initially gave oral steroids (prednisolone 50 mg) for 3 days and treated them locally alternating with triamcinolone and triclosan cream. The rapid im- provement did not last and the patient showed several relapses with erosive lesions on arms and legs. Topical steroids were replaced by tacrolimus 0.1% ointment for both legs and arms and ‘Unna’s paste boots’ (zinc bandages) were applied from the toes to the groin and the hands to the upper arms to prevent the patient from scratching. Approximately 3 g of ointment were used for the treatment of the arms whereas about 4 g were needed for each leg. The bandage was changed every second day. To monitor for possible systemic resorption of tacrolimus, we determined blood levels after 5 days of treatment. To our surprise, serum levels reached 12.9  g/l, which corresponds to a high-dose immunosuppression with tacrolimus. Blood was drawn in the morning prior to the next application of tacrolimus ointment. How- ever, there is a potential bias due to contamination with superficial ointment residues. Tacrolimus acts as an inhibitor of calcineurin and is used sys- temically as a potent immunosuppressive drug enhancing graft sur- vival after organ transplantation. Recently, it has become available for topical use as an ointment. It has been shown to be effective in the treatment of atopic dermatitis. In contrast to topical glucocor- ticosteroids it does not induce skin atrophy and telangiectasias. Its relatively large molecular size and high lipophilicity limit diffusion through skin and into the bloodstream. Percutaneous absorption of tacrolimus is higher in lesional skin as opposed to healthy skin and, therefore, the drug will be taken up at decreasing quantities as le- sions begin to heal [1]. Several studies have evaluated systemic tacrolimus levels after topical application. Ruzicka et al. [2] conducted a randomized, double-blind, multicenter study in 213 patients with moderate to severe atopic dermatitis to compare 0.03, 0.1 and 0.3% tacrolimus ointment. The ointment was applied twice daily. The highest blood concentration was 4.9 ng/ml which was reported in the group re- ceiving 0.3% tacrolimus. Downloaded by: University of Cambridge 149.126.76.97 - 8/14/2015 8:34:30 AM