Significant Systemic Absorption of Tacrolimus After Topical Application in a Patient With Lamellar Ichthyosis

Lamellar ichthyosis (LI) (Online Mendelian Inheritance in Man [OMIM] database No. 242300), usually inherited in an autosomal recessive fashion, is characterized by nonbullous erythroderma and scaling at birth, occasionally with a collodion membrane. Most individuals with LI express mutations in the gene encoding transglutaminase-1 (TGM1), which has been mapped to chromosome 14q11.2.¹ These patients have a reduced barrier function with increased transepidermal water loss values.² Their increased skin permeability may result in intoxication by cutaneous absorption of substances applied to the skin. Indeed, systemic salicylate toxic effects have been reported in a patient with LI after topical application.³ A recent report described 3 children with Netherton syndrome (OMIM 256500), a keratinizing disorder characterized by trichorrhesis nodosa, congenital ichthyosiform erythroderma, and an atopic diathesis, treated with 0.1% tacrolimus ointment who percutaneously absorbed a significant amount of the drug, but without adverse effects.⁴

Our patient was born at term with a collodion membrane and ectropion. By age 2 weeks, lamellar-like scaling developed. The collodion membrane sloughed completely by age 2 months leaving persistent erythema. Supporting the diagnosis of LI, genetic testing of cells obtained from the patient's buccal mucosa revealed mutations occurring in maternally and paternally derived TGM1 (A2526G and A2291C, respectively).

Initial treatment included moisturization and humidification of ambient air. Over the next 2 years, treatments with propylene glycol and various combinations of keratolytics were tried, all with disappointing results. At age 28 months, the patient developed marked pruritus unresponsive to antihistamines and topical corticosteroids. The patient's parents became aware of a recent report indicating that topical 0.1% tacrolimus ointment dramatically improved the cutaneous manifestations of Netherton syndrome⁵ and requested that treatment with the drug be tried in their daughter. Topical 0.1% tacrolimus ointment (Protopic; Fujisawa Healthcare Inc, Deerfield, Ill) was applied to 100% of the body surface area twice daily. Over the next 7 weeks the patient experienced a dramatic improvement, with marked thinning of scales, decreased erythema, resolved pruritus, and substantial clearing on her face and trunk.

Seven weeks after the start of therapy a total of 480 g had been applied, and the tacrolimus blood level was measured. The parents were instructed to avoid applying the medication to the right antecubital fossa for 5 days prior to phlebotomy. The whole-blood tacrolimus level was 19.3 ng/mL 3 hours after application (therapeutic trough range in patients undergoing solid organ transplantation, 5-20 ng/mL). After discussion with colleagues in hematology and oncology regarding the possibility of a complicating Epstein-Barr viral infection and the potential for development of lymphoma, we opted to discontinue tacrolimus treatment. However, this discouraged the patient's family because of her significant improvement while under tacrolimus treatment. Therapy was reinstituted with application twice daily every other day.

Two weeks later an additional 60 g of tacrolimus had been applied, and the drug level was again measured. Again, the ointment was not applied to the antecubital fossa for 5 days prior to testing, and the whole-blood tacrolimus level was 7.4 ng/mL. The frequency of applications was decreased to twice daily every third day for the next 2 weeks. During this time an additional 45 g of drug was applied resulting in a whole-blood tacrolimus level of 5.8 ng/mL. In spite of elevated tacrolimus whole-blood levels, our patient did not experience any adverse clinical events.

Topical tacrolimus is a macrolide immunosuppressant recently approved by the Food and Drug Administration for the treatment of moderate to severe atopic dermatitis.⁶ The drug has become an important therapeutic agent in the treatment of atopic dermatitis for children as young as 2 years. The clinical utility of systemic tacrolimus treatment is limited because of potentially severe adverse effects such as hyperkalemia, nephrotoxicity, neurotoxicity, increased risk of neoplasia (particularly lymphoma), hypertension, and infections.⁷ However, clinical trials of topical tacrolimus treatment in patients with atopic dermatitis revealed essentially negligible absorption and undetectable systemic drug levels.^{8 - 9}

In contrast, patients with Netherton syndrome had a dramatic clinical response paralleling increasing cutaneous absorption.⁴ Interestingly, although these patients developed elevated systemic levels of drug, no adverse outcomes were noted. Our patient also had significant drug absorption that correlated with marked clinical improvement. It seems reasonable to assume that other patients with barrier function defects may be treated with this drug and may also be at increased risk of developing significantly elevated systemic tacrolimus levels. We report this case to alert other physicians and to stress the need for monitoring blood levels of this drug until further investigations are performed.