Tacrolimus in Dermatology—Pharmacokinetics, Mechanism of Action, Drug Interactions, Dosages, and Side Effects: Part I

Authors

  • Virendra N. Sehgal MD,

    1. From the Dermato-Venereology (Skin/VD) Centre, Sehgal Nursing Home, Panchwati, Azadpur, Delhi;1the Skin Institute and School of Dermatology, Greater Kailash, New Delhi;2 and the Department of Dermatology, Venereology and Leprology, Institute of Medical Education and Research, Chandigarh, India3
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  • 1 Govind Srivastava MD,

    1. From the Dermato-Venereology (Skin/VD) Centre, Sehgal Nursing Home, Panchwati, Azadpur, Delhi;1the Skin Institute and School of Dermatology, Greater Kailash, New Delhi;2 and the Department of Dermatology, Venereology and Leprology, Institute of Medical Education and Research, Chandigarh, India3
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  • and 2 Sunil Dogra MD, DNB 3

    1. From the Dermato-Venereology (Skin/VD) Centre, Sehgal Nursing Home, Panchwati, Azadpur, Delhi;1the Skin Institute and School of Dermatology, Greater Kailash, New Delhi;2 and the Department of Dermatology, Venereology and Leprology, Institute of Medical Education and Research, Chandigarh, India3
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Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond), Dermato-Venereology (Skin/VD) Centre, Sehgal Nursing Home, A/6, Panchwati, Delhi-110 033 India
E-mail: drsehgal@ndf.vsnl.net.in

Abstract

The advent of tacrolimus at the end of the preceding century in the armamentarium of atopic dermatitis management was hailed as a breakthrough advance. It was, therefore, thought worthwhile to precisely review its origin and mechanism of action. Its topical application in the form of 0.03% to 0.1% ointments is rapidly effective and safe in pediatric and adult patients. Its use in atopic dermatitis ever since has been approved in Japan, the United States, Europe, and the Indian subcontinent. Thus, its local immunosuppressive action was fairly intriguing. Accordingly, its indications/uses were extended to cover several inflammatory dermatoses. Vitiligo, psoriasis, alopecia areata, contact hypersensitivity, lichen planus, pyoderma gangrenosum, ichthyosis linearis circumflexa, and skin grafting/transplant are a few unapproved indications and uses, in addition to miscellaneous dermatoses. At present, its therapeutic efficacy other then atopic dermatitis is confined to case studies, and large studies are warranted. At this point in time, therefore, it is conceivable that tacrolimus use should be carefully evaluated and used only when the conventional treatment has failed to yield favorable results. It deserves sizable caution for use in various dermatologic conditions pending its long-term safety and efficacy data in large patient populations.

Tacrolimus (FK506), a macrolide lactone produced by soil fungus Streptomyces tsukubaensis, was originally used intravenously or orally for prevention of organ rejection after allogenic liver or kidney transplant. Tacrolimus, especially through the topical route of administration, gained entry into therapy for inflammatory dermatoses,1 such as atopic dermatitis and psoriasis, which were found to respond to this therapy without significant risk of toxicity.2 The interest in several other disorders that respond to topical tacrolimus is gaining momentum, and newer uses of the drug have come to light.3–12 Although tall claims about the benefit of tacrolimus in different disorders have been made, it is still premature to comment on the surety of the benefits vis a vis side effects, including risk of the development of cancers.13,14 The present review attempts to succinctly reflect the current pharmacologic status of tacrolimus (part I) and an emerging scenario of its repercussion as a topical immunomodulator in inflammatory dermatoses. Part II of this review will take stock of its approved as well as unapproved indication/uses in sequence as per the literature available thus far.

Inceptional Repercussions

The drug was initially isolated from a product of Streptomyces tsukubaensis in the year 1987. Kino and colleagues15 studied the immunosuppressive effects of this novel drug in vitro, while Sawada and colleagues16 recorded its in vitro effects on the cloned T-cell activation. The initial name, FK506, is attributable to the complex formed by tacrolimus and its binding protein FKBP (FK506-binding protein). It is a white crystalline powder of molecular formula C44H69NO12 (Figure 1).

Figure 1.

Molecular formula for tacrolimus.

FK506 is an 822 kDa immunosuppressant in the macrolide family that is grouped with cyclosporine A.17 Topical tacrolimus was first introduced in Japan in the year 1999, followed by the United Sates in 2000 and Europe in 2001, for the treatment of moderate to severe atopic dermatitis. On March 10, 2005, the US Food and Drug Administration (FDA) issued an alert for health care professionals, advising them to use tacrolimus as well as pimecrolimus only as directed and only after other eczema treatments have failed, due to a possible cancer risk.18

Pharmacokinetics

Topical tacrolimus is sufficiently absorbed when the skin is inflamed. After an application of 0.03% to 0.3% ointment, the peak levels are reached after 3 to 6 hours of application, which may vary from 0.05 to 0.25 ng/mL.19 Although topical tacrolimus penetrates less readily in the intact or healing skin, its absorption is far better than that of cyclosporine A, as the latter has a larger molecular weight (1202.635) compared with tacrolimus (mol weight 822.05).17,20,21 Whole blood level may be monitored, however, to avoid exceeding the safe limit of 5 to 20 ng/mL, which is considered safe according to results from transplant recipients.17 Unlike corticosteroids, tacrolimus is not atrophogenic. At concentrations that had efficacy similar to that of 0.13%clobetasol, it did not cause atrophy of the skin when used to treat inflammatory disorders.22 The oral absorption of tacrolimus is largely incomplete, poor, and very erratic. It varies from 13% to 23% in healthy persons, while it is 7% to 27% in kidney transplant patients and 16% to 28% in adult liver transplant patients. Under fasting conditions, its absorption was maximum. The variability of absorption may be due in part to poor aqueous solubility of the drug in gastric secretions.1,23

Tacrolimus is largely metabolized in the liver by the cytochrome P450 enzyme system via monodemethylation and/or hydroxylation. The drug is then excreted through the bile, which displays most of its metabolites. Less than 1% of the drug is excreted unchanged in the urine.24

Mechanism of Action

Tacrolimus achieves immunosuppression mainly by inhibiting T lymphocyte activation due to inhibition of interleukin 2 (IL-2) transcription, which, in turn, decreases T lymphocyte responsiveness to foreign antigens. Tacrolimus and its binding protein (FKBP) form a complex, which then associates with calcineurin, calcium, and calmodulin.

This results in inhibition of calcineurin phosphatase activity. This controls transcription of genes that code for several inflammatory mediators such as IL-2, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, interferon γ and other interleukins requisite for the development of immune response.25–28 Thus, the early phase of T-cell activation is blocked without the impairment of exogenously administered cytokine response (Figure 2). Furthermore, tacrolimus also inhibits the release of histamine from mast cells and impairs de nova prostaglandin synthesis. It also suppresses the histamine release of the basophile. These actions may reduce pruritus.29–31

Figure 2.

Mechanism of action of tacrolimus.

Drug Interactions

As tacrolimus is metabolized by the cytochrome P450 enzyme system, the drugs that are metabolized either by inhibiting or inducing these enzyme systems may cause either raised or lowered tacrolimus blood/plasma levels (Table). Drugs that alter/impair renal function should be used with caution as tacrolimus impairs the renal system. Furthermore, since tacrolimus produces immunosuppression, the use of live vaccines should be avoided.23,32

Table Table.  Tacrolimus: Drugs that May Alter Tacrolimus Metabolism1,32
ParameterDrugs
Increase of tacrolimus levelsAnticonvulsants: carbamazepine, phenobarbital, phenytoin
 Antibiotics: rifampicin, rifabutin
Decrease of tacrolimus levelsAntifungal: clotrimazole, ketoconazole, fluconazole, itraconazole
 Ca++ channel blockers: diltiazem, nifedipine, nicardipine, verapamil
 Macrolides: erythromycin, clarithromycin, troleandomycin
 Miscellaneous: cyclosporin A, danazol, bromocriptine, cimetidine, methylprednisolone, protease inhibitors

Side Effects and Safety

Apart from mild to moderate burning, erythema, and pruritus, the use of tacrolimus ointment can cause folliculitis,33 acne, Kaposi's varicelliform eruptions, eczema herpeticum, and herpes simplex infections. Increased skin sensitivity to hot and cold and alcohol intolerance have also been reported.1,23 Occurrence of recurrent skin tags,34 rosacea-like granulomatous eruptions,35 rosaceiform dermatitis,36 mucosal hyperpigmentation,37 tinea incognito,38 molluscum contagiosum,39–41 and verruca vulgaris42 have recently been reported. The cutaneous viral infection in particular is alarming and may be caused by local immunosuppression.

Although there is a theoretic concern that topical immunomodulatory therapy with tacrolimus and pimecrolimus may increase the risk of cancer, there is no evidence to date to suggest an increased risk of cutaneous or visceral cancer. The European Agency for the Evaluation of Medicinal Products has not recommended any change in labelling or approval of these topical agents, and a task force of the American Academy of Allergy Asthma and Immunology did not support the black box warning as lymphoma is associated with high-dose systemic therapy, the reported cases are not consistent with lymphoma observed. There may still be clinical situations where such off-label treatment is seen as a lesser risk than available alternatives such as oral administration of an immunosuppressant, and limited data on safety are emerging.

Dosages

Oral tacrolimus has been used in psoriasis in the dosage of 0.1 mg/kg/body weight/d. The plasma levels effective in inducing and maintaining remission range from 0.5 mg to 1.4 ng/mL.43,44 The topical route is a preferred choice; however, due to the benign nature of these dermatoses, and the potentially serious side effects of oral/intravenous tacrolimus confine its use only in transplant patients.

Topically, tacrolimus has been used in 0.03%to 0.1% ointment. In pediatric patients aged 2 years and older, 0.03% is preferred, while in adults and geriatric patients 0.1% may be used 2 times a day. It is not recommended for use in pregnancy and lactation, as its safety has not yet been established.2,45 Although results of combining topical tacrolimus with UV light has been found to be encouraging in vitiligo, carcinogenic adverse effects cannot be ruled out, and long-term follow-up is still required. Currently, patients are simply advised against exposure to natural or artificial sunlight exposure.46

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