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Topical Tacrolimus

S.J. Frankel, BSc and F.A. Kerdel, BSc, MBBS, MD
Departments of Dermatology & Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida, USA

ABSTRACT

Tacrolimus, available for intravenous, oral and now topical administration, is a potent immunosuppressive agent with the ability to block the production of Interleukin-2 (IL-2) and inhibit T-cell proliferation. Originally developed for use in organ transplantation, it is currently being studied for the treatment of inflammatory dermatoses. The US FDA recently approved tacrolimus ointment (Protopic, Fujisawa) for the treatment of atopic dermatitis.

Key Words: tacrolimus, atopic dermatitis, immunosuppressant

Tacrolimus, previously known as FK506, is an 822-KDamacrolide antibiotic produced by the fungus Streptomyces tsukubaensis. It is a powerful immunosuppressant and although itís not structurally related, tacrolimus exhibits selective antilymphocytic activity similar to cyclosporine, an agent that has revolutionized transplantation medicine and the treatment of selected autoimmune disorders. Currently, tacrolimus is emerging as a promising therapeutic alternative for the treatment of a number of dermatological diseases that have in common an aberrant immunologic response. This topical ointment is the first of its kind to be approved by the US FDA (December 2000), 0.1% for the treatment of moderate-to-severe atopic dermatitis in adults, and 0.03% for children older than 2 years of age and for adults who are undergoing long-term intermittent therapy. Phase III trials are underway in Canada, where a New Drug Submission (NDS) was put forward in July 2000. In Japan, Protopic 0.1% was approved in 1999.

Mechanism of Action

Both tacrolimus and cyclosporine interrupt the T-cell receptor mediated signal transduction pathway, which ultimately blocks the production of Interleukin-2 (IL-2) and inhibits T-lymphocyte proliferation. However, in vitro studies have shown that when compared to cyclosporine, tacrolimus exhibits 10-100 times greater immunosuppressive activity.1

During T-cell activation, antigen binds to its specific T-cell receptor causing an increase in intracellular calcium. The calcium ions then bind to the molecule calmodulin resulting in a complex that activates calcineurin. Calcineurin is a calcium dependent serine/threonine phosphatase that dephosphorylates nuclear factor of activated T-cells (NF-AT). Once dephosphorylated, NF-AT translocates from the cytosol into the nucleus, binds to the promoter region of several cytokine genes (i.e., IL-2, IL-3, IL-4, GM-CSF, TNF-alpha), and induces their transcription.1,2

Tacrolimus acts by diffusing into the cytoplasm and binding to an immunophilin intracellular receptor named FK-binding protein (FKBP). The tacrolimus-FKBP complex then binds to calcineurin and physically blocks the entrance of molecules, such as NF-AT, to its active site. Therefore, in the presence of the tacrolimus- FKBP complex, the phosphorylated NF-AT is unable to translocate into the nucleus. This halts the transcription of IL-2 and other cytokines, thus inhibiting T-cell proliferation.1,2

In addition to its action against T-cell proliferation, in vitro tacrolimus demonstrates a direct inhibitory effect on mast cell degranulation. It also seems to inhibit the production of the proinflammatory mediator IL-8 and the IL-8 receptor. As well, it decreases the binding of IL-8 to its receptor on keratinocytes. Finally, in vitro studies also suggest that tacrolimus enhances the action of the tumor suppressor gene p53.3

Unlike cyclosporine, a molecule which seems to be too large to penetrate human skin, tacrolimus is active topically and appears to target epidermal leukocytes, and antigen presenting epidermal dendritic cells. In vitro and in vivo studies have shown that topical tacrolimus down-regulates the expression of the high-affinity receptor for immunoglobulin E (IgE) and the costimulatory molecule CD80 in epidermal dendritic cells. It may also interfere with epidermal cytokine networks and TH1/TH2 lymphocyte balance. Additional studies are certainly warranted, however, these mechanisms may begin to explain the efficacy of topical tacrolimus for atopic dermatitis.1,4

Pharmacokinetics

When applied to intact human skin, in vitro studies have demonstrated that tacrolimus is not readily absorbed. However, on inflamed or damaged skin, it is absorbed in sufficient amounts to be topically active. The agent is metabolized in the liver by Cytochrome P4503A4 and is eliminated almost completely in the bile.1,3,5

Indications & Clinical Trials

Perhaps most exciting is the finding that topical preparations of tacrolimus, in contrast to cyclosporine, are effective for the treatment of certain skin disorders including atopic dermatitis and allergic contact dermatitis. Based on the results of an open trial in 1994, Nakagawa, et al, first reported the safety and efficacy of topical tacrolimus against atopic dermatitis.14 In this trial, all patients had improved disease severity by day 21. Furthermore, the highest recorded blood level of tacrolimus was 0.9ng/ml, which is significantly lower than the levels (5-20ng/ml) obtained during systemic therapy.6 Since that time, multiple controlled and uncontrolled studies have confirmed the safety and efficacy of topical tacrolimus for atopic dermatitis (see Table 1). For example, Alaiti, et al, demonstrated the efficacy of twice daily application of tacrolimus 0.3% ointment over 8 days in 31 adults and 8 children with moderate-to-severe atopic dermatitis. In this study, no systemic accumulation of tacrolimus was observed, 95% of patients showed at least good improvement, and no drugrelated changes in laboratory profile were noted.7

Additionally, in a randomized, double-blind, multicenter trial that compared 0.03%, 0.1% and 0.3% ointment in 213 patients with moderate-to-severe atopic dermatitis, statistically significant improvement was noted in all treatment groups when compared with the placebo group. However, differences between the three treatment groups were not statistically significant. In concordance with prior observations, the only notable adverse event during topical tacrolimus therapy was irritation at the treatment site. Furthermore, throughout the investigation most treatment group patients maintained blood concentrations below 0.25ng/ml.8

Nevertheless, it should be noted that in one study to examine tacrolimus concentrations in blood during topical treatment of atopic dermatitis, a blood concentration of 20ng/ml was recorded in an erythrodermic patient 6 hours after receiving one application of 10g of ointment with a tacrolimus dosage of 1mg/gm. Although the blood concentrations decreased to 2.9ng/ml by 72 hours and no systemic side effects were observed, this finding may support the utility of laboratory monitoring during topical tacrolimus therapy, especially in patients with an extensively impaired skin barrier.9

Because atopic dermatitis is a chronic, relapsing condition in which continuous or repeated use of medications is quite common, an open-label, non-comparative study was recently performed to investigate the safety and efficacy of 0.1% tacrolimus ointment for long-term treatment. Consistent with the results of earlier short-term trials, local irritation (e.g., burning, pruritus, erythema) seemed to be the only adverse event clearly related to the use of tacrolimus ointment, and no systemic side effects were apparent. By 12 months, 86% of patients experienced marked improvement or clearance of disease.10 Finally, and perhaps most importantly, the safety and efficacy of twice daily application of tacrolimus ointment for pediatric patients was demonstrated in a double-blind, vehicle-controlled multicenter trial of children aged 7-16 years with moderate-to-severe atopic dermatitis.11 This may have important implications for the future approach to atopic dermatitis, the most common chronic skin disease in children.

With regard to allergic contact dermatitis in human volunteers, 0.01-0.1% preparations of tacrolimus suppressed the allergic reactions to dinitrochlorobenzene (DNCB) when compared with placebo.12

Study Subjects Dosage and Regime n % improvement Side Effects

Randomized, double-blind, multicenter8

213 adult patients

  • 0.03% bid x 3 wks
  • 0.1% bid x 3 wks
  • 0.3% bid x 3 wks
  • Vehicle bid x 3 wks

  • 51
  • 54
  • 54
  • 54

  • 75%
  • 83%
  • 66.7%
  • 22.5%

Burning at site; No systemic adverse events noted

Open-label, twocenter, phase I7

39 patients aged 5-75 years

0.3% for 8 days, once/day on days 1 & 8
bid on days 2-7

39

95%

Burning at site; Vasodilation (flushing/warmth)

Open-label, noncomparative10

316 patients aged ≥ 18 years

0.1% bid

  • x 6 mos
  • x 12 mos

  • 200
  • 116

  • 81%
  • 86%

Burning, pruritus, erythema

Double-blind, vehicle controlled, multicenter11

180 patients aged 7-16 years

  • 0.03% bid x 22 days
  • 0.1% bid x 22 days
  • 0.3% bid x 22 days
  • Vehicle bid x 22 days

  • 43
  • 49
  • 44
  • 44

  • 72%
  • 77%
  • 81%
  • 26%

No systemic adverse events noted

Table 1: A review of some clinical studies done to determine the efficacy of tacrolimus ointment for the treatment of moderate-to-severe atopic dermatitis.

Drug Interactions

Like cyclosporine, tacrolimus is metabolized by the cytochrome P450 system. Therefore, similar to the multitude of potential drug interactions noted with cyclosporine therapy, any substance that affects cytochrome P450 activity may affect the pharmacokinetics of tacrolimus. This list includes, but is not limited to, erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol, which may increase tacrolimus blood concentrations. On the other hand, rifampin has been shown to decrease tacrolimus blood concentrations. Finally, data has suggested that tacrolimus may interact with nonsteroidal antiinflammatory drugs resulting in an increased risk of nephrotoxicity.13

Adverse Effects

Topically applied tacrolimus is well tolerated and no systemic side effects have been reported. Burning and stinging are the most commonly documented adverse events associated with the ointment, and mild skin irritation that recedes with time has been noted in a minority of patients.8,10 Importantly, unlike corticosteroids, tacrolimus does not induce atrophogenic effects, and recent in vivo studies demonstrate that it does not affect collagen synthesis.1

Conclusion

Protopic is the first of a new generation of topical immunomodulators that bring about clinical improvement by modulating the patientís immune response, and is the first to be recommended for approval by the US FDA. It has proven to be safe and effective for the treatment of atopic dermatitis, and unlike cyclosporine, topical preparations of tacrolimus demonstrate efficacy. Of major importance is the possibility that this drug, in contrast to corticosteroids, may not induce skin atrophy. Protopic is the first of a new generation of topical immunomodulators that bring about clinical improvement by modulating the patientís immune response, and is the first to be recommended for approval by the US FDA. It has proven to be safe and effective for the treatment of atopic dermatitis, and unlike cyclosporine, topical preparations of tacrolimus demonstrate efficacy. Of major importance is the possibility that this drug, in contrast to corticosteroids, may not induce skin atrophy.

In Canada, 30gm of an extemporaneously compounded topical formulation of 0.1% tacrolimus is available for $40CDN. Fujisawa has not yet determined pricing for its new product in the US. They plan to begin marketing Protopic in the spring of 2001.

References

  1. Ruzicka T, Assmann T, Homey B. Tacrolimus: the drug for the turn of the millennium? Arch Dermatol 135(5):574-80 (1999 May).
  2. Griffith JP, Kim JL, Kim EE, et al. X-ray structure of calcineurin inhibited by the immunophilin- immunosuppressant FKBP12-FK506 complex. Cell 82:507-22 (1995 Aug).
  3. Lauerma AL, Granlund H, Reitamo S. Use of the newer immunosuppressive agents in dermatology. BioDrugs 8:96-106 (1997).
  4. Bieber T. Topical tacrolimus (FK 506): A new milestone in the management of atopic dermatitis. J Allergy Clin Immunol 102(4 Pt 1):555-7 (1998 Oct).
  5. Meigassner JG, Stutz A. Immunosuppressive macrolides of the type FK 506: A novel class of topical agents for treatment of skin diseases? J Invest Dermatol 98(6):851-5 (1992 Jun).
  6. Fleischer AB. Atopic dermatitis: An update for the next millenium. J Allergy Clin Immunol 104(3):S126-30 (1999).
  7. Alaiti S, Kang S, Fiedler VC, et al. Tacrolimus (FK506) ointment for atopic dermatitis: A phase I study in adults and children. J Am Acad Dermatol 38:69-76 (1998 Jan).
  8. Ruzicka T, Bieber T, Schopf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. N Engl J Med 337(12):816-21 (1997 Sep).
  9. Kawashima M, Nakagawa H, Ohtsuki M, Tamaki K, Ishibashi Y. Tacrolimus concentrations in blood during topical treatment of atopic dermatitis. Lancet 348(9036):1240-1 (1996 Nov).
  10. Reitamo S, Wollenberg A, Schopf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol 136:999-1006 (2000 Aug).
  11. Boguniewicz M, Fiedler V, Raimer S, et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J All Clin Immunol 102(4):637-44 (1998 Oct).
  12. Lauerma AI, Maibach HI, Graunlund H, Erkko P, Kartamaa M, Stubb S. Inhibition of contact allergy reactions by topical FK 506. Lancet 340(8818):556 (1992 Aug).
  13. Mignat C. Clinically significant drug interactions with new immunosuppressive agents. Drug Safety 16(4):267-78 (1997).
  14. Nakagawa H, Etoh T, Ishibashi Y, et al. Tacrolimus ointment for atopic dermatitis. Lancet 344(8926):883 (1994 Sep).

In this issue:

  1. Topical Tacrolimus
  2. The Use Of Interleukins For Advanced Melanoma
  3. Update on Drugs and Drug News - Number 4 2000