Trip Answers

Two RCTs studying tacrolimus ointment for atopic dermatitis were found in the Cochrane Library. The first was a randomized double-blind, multicenter study that compared 0.03%, 0.1%, and 0.3% tacrolimus ointment with vehicle alone in 213 patients with moderate-to-severe atopic dermatitis over three weeks. ¹ The primary endpoint was the change in the summary score for erythema, edema and pruritus between the first and last days of treatment. The median percentage decrease in summary score for the tacrolimus groups was 75% - the differences between groups not being statistically significant. This compared to a 22.5% decrease in summary score for the 54 patients receiving vehicle alone. The authors of the study report that throughout the study most patients in all three tacrolimus groups had blood concentrations of tacrolimus below 0.25ng per mL. The highest blood concentration was 4.9 ng per mL that was reported in the group receiving 0.3% tacrolimus. The only adverse event reported at greater frequency than those of vehicle alone was a sensation of burning at the site of application.

A second RCT examined tacrolimus ointment at varying concentration (0.03, 0.1 and 0.3%) against vehicle for up to 22 days with two week follow up in 180 pediatric patients with moderate to severe atopic dermatitis. ² Efficacy was assessed according to the Physician’s Global Evaluation of clinical response measure. 70% of patients receiving tacrolimus ointment had a marked to excellent improvement as opposed 38% of the vehicle group. The authors note that no serious systemic adverse events were noted and systemic absorption was minimal.

A Medline search yielded three further studies of longer duration. Twice daily application of 0.1% tacrolimus ointment in adults in an open-label non-comparative study with 6 to 12 months follow-up was reported in the literature in 2000.³ Safety assessments included monitoring of adverse event, clinical laboratory values and tacrolimus blood concentrations. Local irritation such as burning, pruritus and erythema occurred in 47%, 24% and 12% of patients respectively but tended only to occur when initiating treatment. Laboratory values showed no marked changes over time. Systemic absorption was minimal, with the maximum tacrolimus concentration being less than 1 ng.mL in 76% of patients.

Most recently two further double-blind trials investigating tacrolimus ointments versus vehicle over 12 weeks were reported.⁴ These studies examined mean percent body surface area (%BSA) affected at baseline and after treatment. They concluded that the 0.1% concentration was more effective than the 0.03%, particularly in patients with severe disease and/or extensive BSA involvement at baseline and the treatment was effective on all skin regions including the head and neck.

Another topical preparation currently being examined is ascomycin macrolactam (SDZ ASM 981). The Cochrane library has a small study comparing the safety and efficacy of 1% SDZ ASM 981 cream and a matching placebo cream in the treatment of patients with moderate atopic dermatitis.⁵ The study was a randomized, double-blind, placebo-controlled, right-and-left comparison study. Topical 1% SDZ ASM 981 cream was applied twice daily (n=16) or once daily (n=18) and compared with a corresponding placebo cream base. Efficacy was measured against the Atopic Dermatitis Severity Index (ADSI) and safety was evaluated during the course of the study. Within 3 weeks of topical therapy the twice daily treated sites showed a 71.9% reduction in ADSI score compared with 10.3% in placebo sites. Efficacy in the once daily group was lower with mean reductions of 37.7% and 6.2% respectively. The authors note no clinically relevant drug-related adverse effects and state that more elaborate phase 2 and 3 trials are under way to fully investigate the potential of this treatment.

A more recent study was conducted to determine appropriate dosage for phase III trials of SDZ ASM 981.⁶ 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0%, matching vehicle cream or internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to three weeks. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. The authors report that the efficacy plateau was not reached within 3 weeks treatment. The local tolerability profile of the 1.0 % cream was similar to that of lower concentrations. Few systemic adverse events were reported during the study.

The systemic exposure of 1.0% SDZ ASM 981 cream has also been studied in a small group of children aged 1-4 years.⁷ The treatment showed variable efficacy over three weeks but blood concentrations of SDZ ASM 981 were consistently low even in children with extensive affected skin area.

Oral cyclosporin A has also been used successfully in the treatment of atopic dermatitis.^8-14 Several efforts have been made to develop a topical cyclosporin formulation in order to avoid systemic adverse events but these have met with limited success.^15,16 Recently interest has renewed in this approach with studies examining the efficacy of microemulsions of cyclosporin. ^17,18

1. Ruzicka T et al, A short-term trial of tacrlimus ointment for atopic dermatitis, NEJM 1997, 337(12); 816-821.
2. Boguniewicz M et al, A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group, Journal of Allergy & Clinical Imunology 1998, 102, 637-44.
3. Reitamo S et al, Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study group, Archives of Dermatology 2000, 136 (8): 999-1006.
4. Hanifin JM et al, Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: partI efficacy, Journal of the American Academy of Dermatology 2001, 44(1 Suppl): S28-38.
5. Van Leent EJ et al, Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis, Archives of Dermatology 1998, 134(7), 805-9.
6. Luger T et al, SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis, British Journal of Dermatology 2001, 144(4):788-94.
7. Harper et al, First experience of topical SDZ ASM 981 in children with atopic dermatitis, British Journal of Dermatology 2001, 144(4): 781-7.
8. Harper JI, Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy, British Journal of Dermatology 2000, 142(1), 52-8.
9. Granlund H, Comparison of the influence of cyclosporine and topical betamethasone-17,21-dipropionate treatment on quality of life in chronic hand eczema, Acta Dermato-Venerelogica 1997, 77(1), 54-8.
10. Zonneveld IM et al, The long-term safety and efficacy of cyclsporin in sever refractory atopic dermatitis: a comparison of two dosage regimes, British Journal of Dermatology 1996, 135 suppl 48, 15-20.
11. Van Joost T et al, Cyclosporin in atopic dermatitis: a multicentre placebo-controlled study, British Journal of Dermatology 1994, 130(5), 634-40.
12. Munro CS, Maintenance treatment with cyclosporin in atopic eczema, British Journal of Dermatology, 1994, 130(3), 376-80.
13. Sowden JM, Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis, Lancet 1991, 338 (8760), 137-40.
14. Salek MS et al, Cyclosporin greatly improves the quality of life of adults with severe atopic dermatitis. A randomized, double-blind, placebo-controlled trial, British Journal of Dermatology 1993, 129(4), 422-30.
15. De Rie MA et al, Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis 1991, 71(5), 452-4.
16. De Prost et al, Randomised double-blind placebo-controlled trail of local cyclsporin in atopic dermatitis, Acta Dermato-Venereologica. Supplementum 1989, 144, 136-8.
17. Zurbriggen B et al, Comparison of two formulations of cyclosporin A in the treatment of severe atopic dermatitis. A double-blind, single-centre, cross-over pilot study, Dermatology 1999, 198(1), 56-60.
18. Czech W, A body-weight-independent dosing regimen of cyclsporine microemulsion is effective in severe atopic dermatitis and improves quality of life, Journal of the American Academy of Dermatology 2000, 42(4), 653-9.