Low But Detectable Serum Levels of Tacrolimus Seen With the Use of Very Dilute, Extemporaneously Compounded Formulations of Tacrolimus Ointment in the Treatment of Patients With Netherton Syndrome | Congenital Defects | JAMA Dermatology | JAMA Network
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Figure. 
Patient 1 response to treatment with topical tacrolimus ointment, 0.01%, twice daily for 1 week. A, Untreated right arm. B, Treated left arm demonstrating decreased erythema and scaling.

Patient 1 response to treatment with topical tacrolimus ointment, 0.01%, twice daily for 1 week. A, Untreated right arm. B, Treated left arm demonstrating decreased erythema and scaling.

1.
Chavanas  S, Bodemer  C, Rochat  A,  et al.  Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.  Nat Genet. 2000;25:141-142. PubMedGoogle ScholarCrossref
2.
Bens  G, Boralevi  F, Buzenet  C, Taieb  A.  Topical treatment of Netherton's syndrome with tacrolimus ointment without significant systemic absorption.  Br J Dermatol. 2003;149:224-226. PubMedGoogle ScholarCrossref
3.
Oji  V, Beljan  G, Beier  K, Traupe  H, Luger  TA.  Topical pimecrolimus: a novel therapeutic option for Netherton syndrome.  Br J Dermatol. 2005;153:1067-1068. PubMedGoogle ScholarCrossref
4.
Boguniewicz  M, Fiedler  VC, Raimer  S,  et al; Pediatric Tacrolimus Study Group.  A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children.  J Allergy Clin Immunol. 1998;102:637-644. PubMedGoogle ScholarCrossref
5.
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. 1998;38:69-76. PubMedGoogle ScholarCrossref
6.
Hanifin  JM, Ling  MR, Langley  R, Breneman  D, Rafal  E.  Tacrolimus ointment for the treatment of atopic dermatitis in adult patients, 1: efficacy.  J Am Acad Dermatol. 2001;44:S28-S38. PubMedGoogle ScholarCrossref
7.
Allen  A, Siegfried  E, Silverman  R,  et al.  Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome.  Arch Dermatol. 2001;137:747-750. PubMedGoogle Scholar
8.
Allen  DM, Esterly  NB.  Significant systemic absorption of tacrolimus after topical application in a patient with lamellar ichthyosis.  Arch Dermatol. 2002;138:1259-1260. PubMedGoogle ScholarCrossref
Research Letter
October 2006

Low But Detectable Serum Levels of Tacrolimus Seen With the Use of Very Dilute, Extemporaneously Compounded Formulations of Tacrolimus Ointment in the Treatment of Patients With Netherton Syndrome

Arch Dermatol. 2006;142(10):1362-1363. doi:10.1001/archderm.142.10.1362

Netherton syndrome (Online Mendelian Inheritance in Man No. 256500 [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=256500]) is a rare, autosomal recessive genetic disorder characterized by infantile erythroderma, a chronic eczematous dermatitis, ichthyosis linearis circumflexa, sparse brittle hair with hair-shaft abnormalities (trichorrhexis invaginata), variable immunologic defects, and failure to thrive. Recent genetic studies in patients with Netherton syndrome have identified mutations in the SPINK5 gene, which encodes the serine protease inhibitor Kazal type 5,1 that are thought to result in impaired epidermal barrier function, increased transepidermal water loss, increased susceptibility to infection, and increased permeability to exogenous agents.

The dermatologic manifestations of Netherton syndrome can be severe, with unremitting pruritus as well as chronic erythroderma. While topical steroids have been of only limited benefit, recent studies have demonstrated clinical improvement with the use of topical calcineurin inhibitors,2,3 including topical tacrolimus. Although several studies have documented normal (undetectable) serum levels of tacrolimus in otherwise healthy children and adults receiving topical tacrolimus therapy for atopic dermatitis,4-6 case reports highlight significantly elevated serum tacrolimus levels that approach or exceed therapeutic serum trough levels recommended for organ transplant recipients (5-20 mg/mL) in children with Netherton syndrome7 and lamellar ichthyosis8 treated with topical tacrolimus. Despite elevated serum levels, manifestations of systemic toxic effects have not been described in patients receiving topical tacrolimus.

We report our experience with 3 patients with Netherton syndrome who were treated with topical tacrolimus ointment between October 2001 and October 2003. Owing to concerns over possible significant systemic absorption, commercially available tacrolimus ointment (0.1% or 0.03%) was extemporaneously compounded in hydrophilic ointment to create more dilute formulations. Serum tacrolimus levels, blood cell counts, and renal and liver function were monitored regularly during therapy.

Report of Cases

Case 1. A 4½-year-old girl initially received treatment with a limited topical application of tacrolimus ointment, 0.01%, to the left arm twice daily (Figure). Although moderate clinical improvement was noted after 5 days, the serum tacrolimus level was elevated at 4.2 ng/mL. The frequency of application was decreased to once daily for 2 weeks, which maintained clinical improvement while reducing the serum tacrolimus level to less than 1.5 ng/mL. Subsequently, twice-daily application of tacrolimus ointment, 0.005%, to the face and hands resulted in significant improvement in scaling and erythema within 1 week. With continued treatment, serum levels of tacrolimus were 5.4 ng/mL at 1 month, 2.0 ng/mL at 6 months, and 2.9 ng/mL at 12 months. Tachyphylaxis subsequently became evident, and the patient discontinued therapy.

Cases 2 and 3. Identical 8½-year-old twin girls initially applied tacrolimus ointment, 0.005%, to the face and neck twice daily. Rapid clinical improvement was observed within 1 week, and serum levels of tacrolimus remained below 3 ng/mL at 1 week, 1 month, and 3 months. Tachyphylaxis subsequently became evident despite increases in topical tacrolimus concentration to 0.0075%, 0.01%, and 0.03%, so therapy was discontinued.

In all 3 patients, monitoring of complete blood cell counts, liver function tests, and levels of electrolytes, serum urea nitrogen, and creatinine failed to disclose any abnormalities during treatment.

Comment

Dilute, extemporaneously compounded formulations of topical tacrolimus may represent a clinically efficacious, short-term adjunct to therapy in patients with Netherton syndrome, although the effects of ongoing, long-term use are unknown. There is significant potential for substantial systemic absorption manifesting as elevated serum levels of tacrolimus, even when the treatment involves application to only limited body surface areas. The development of tachyphylaxis, which occurs with long-term use of topical steroids, also appears to be a concern with the use of topical tacrolimus among patients with Netherton syndrome. Patients with Netherton syndrome who are using topical tacrolimus should receive periodic monitoring of serum tacrolimus levels, liver function, and renal function during therapy. Use of tacrolimus ointment in patients with Netherton syndrome should likely be reserved for the short-term management of flares and should be considered only when the benefits clearly outweigh the risks.

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Article Information

Correspondence: Dr Yan, Pediatric Dermatology, Children's Hospital of Philadelphia, 324 S 34th St, Philadelphia, PA 19104 (yana@email.chop.edu).

Financial Disclosure: Dr Yan has served as a paid consultant for Astellas Pharma Inc, Tokyo, Japan.

References
1.
Chavanas  S, Bodemer  C, Rochat  A,  et al.  Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.  Nat Genet. 2000;25:141-142. PubMedGoogle ScholarCrossref
2.
Bens  G, Boralevi  F, Buzenet  C, Taieb  A.  Topical treatment of Netherton's syndrome with tacrolimus ointment without significant systemic absorption.  Br J Dermatol. 2003;149:224-226. PubMedGoogle ScholarCrossref
3.
Oji  V, Beljan  G, Beier  K, Traupe  H, Luger  TA.  Topical pimecrolimus: a novel therapeutic option for Netherton syndrome.  Br J Dermatol. 2005;153:1067-1068. PubMedGoogle ScholarCrossref
4.
Boguniewicz  M, Fiedler  VC, Raimer  S,  et al; Pediatric Tacrolimus Study Group.  A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children.  J Allergy Clin Immunol. 1998;102:637-644. PubMedGoogle ScholarCrossref
5.
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. 1998;38:69-76. PubMedGoogle ScholarCrossref
6.
Hanifin  JM, Ling  MR, Langley  R, Breneman  D, Rafal  E.  Tacrolimus ointment for the treatment of atopic dermatitis in adult patients, 1: efficacy.  J Am Acad Dermatol. 2001;44:S28-S38. PubMedGoogle ScholarCrossref
7.
Allen  A, Siegfried  E, Silverman  R,  et al.  Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome.  Arch Dermatol. 2001;137:747-750. PubMedGoogle Scholar
8.
Allen  DM, Esterly  NB.  Significant systemic absorption of tacrolimus after topical application in a patient with lamellar ichthyosis.  Arch Dermatol. 2002;138:1259-1260. PubMedGoogle ScholarCrossref
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