What is the mechanism of action of tacrolimus (FK506) 0.03% ointment?

From the Guidelines

Tacrolimus (FK506) 0.03% ointment works as an immunosuppressant by inhibiting calcineurin, a phosphatase enzyme crucial for T-cell activation, thereby reducing the inflammatory response in conditions like atopic dermatitis and psoriasis. The mechanism of action involves the binding of tacrolimus to FK-binding proteins within T-cells, forming a complex that blocks calcineurin's ability to dephosphorylate the nuclear factor of activated T-cells (NFAT) 1. This prevents NFAT from entering the nucleus and initiating transcription of pro-inflammatory cytokines like interleukin-2, tumor necrosis factor-alpha, and interferon-gamma.

Key Points

• Tacrolimus is suitable for sensitive areas and long-term use due to its lack of skin atrophy compared to topical corticosteroids 1.
• The 0.03% concentration is typically used for milder cases and in pediatric patients, while the 0.1% strength is reserved for more severe or resistant cases in adults 1.
• Tacrolimus begins working within days of application, though maximum benefit may take 1-2 weeks of consistent use.
• The medication should be applied as a thin layer to affected areas twice daily until symptoms improve.

Evidence Summary

The most recent and highest quality study, published in 2023, provides high certainty evidence to strongly recommend the use of tacrolimus 0.1% and 0.03% ointments to treat atopic dermatitis patients 1. This study, along with others, supports the efficacy and safety of tacrolimus in reducing inflammation and improving symptoms in atopic dermatitis and psoriasis, with a low absolute risk of lymphoma associated with its use 1.

From the FDA Drug Label

1. 1 Mechanism of Action Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

The mechanism of action of tacrolimus 0.03% ointment is through the inhibition of calcineurin, which prevents the activation of T-lymphocytes and B-cells, resulting in immunosuppression. Key steps in this process include:

• Binding to FKBP-12
• Inhibition of calcineurin phosphatase activity
• Prevention of NF-AT and NF-κB translocation
• Inhibition of cytokine expression and production 2

From the Research

Mechanism of Action of Tacrolimus 0.03% Ointment

The mechanism of action of tacrolimus (FK506) 0.03% ointment involves the down-regulation of antigen-specific T-cell activities and associated proinflammatory cytokine production 3. This is achieved through the inhibition of calcineurin, a phosphatase that plays a crucial role in the activation of T-cells 4.

Key Features of Tacrolimus 0.03% Ointment

• The ointment is a topical immune suppressant that does not cause dermal atrophy, unlike hydrocortisone derivatives 4
• It has a rapid onset of action and exerts sustained therapeutic effects, with an efficacy similar to that of moderate to potent topical corticosteroids 3
• The 0.03% concentration is effective in treating moderate to severe atopic dermatitis in children, with twice daily application resulting in greater improvement than once daily application 5

Comparison with Other Treatments

• Tacrolimus 0.03% ointment is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis 5
• Tacrolimus 0.1% ointment has superior efficacy to fluticasone 0.005% ointment for twice-daily treatment of adults with moderate to severe facial atopic dermatitis 6
• Tacrolimus has higher efficacy and better tolerance than pimecrolimus in the treatment of atopic dermatitis 7