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Topical Pimecrolimus

A Review of its Clinical Potential in the Management of Atopic Dermatitis

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Summary

Abstract

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is a nonsteroid, has anti-inflammatory activity, and has demonstrated efficacy in reducing symptoms of atopic dermatitis in adult and paediatric patients when applied topically.

Compared with vehicle, topical pimecrolimus 1.0% cream was significantly more effective at reducing symptoms of atopic dermatitis, as measured by the Eczema Area and Severity Index (EASI), in infants aged 3 to 23 months, children aged 2 to 17 years and adults. The median reductions from baseline in the total EASI score in adults after treatment with pimecrolimus 1.0% or corresponding vehicle twice daily for 3 weeks were 47 and 0%, respectively. In infants and children, treatment with pimecrolimus 1.0% twice daily for 6 weeks resulted in significant decreases in mean EASI scores compared with vehicle.

The severity of pruritus was significantly reduced in patients of all age groups after topical treatment with pimecrolimus 1.0% cream. Compared with vehicle, the incidence of eczematous flares was also reduced by intermittent long-term use of topical pimecrolimus 1.0% in adults, children and infants. Sixty percent of children treated with pimecrolimus for 1 year completed the first 6 months of treatment without experiencing a flare, compared with 35% of patients who received vehicle. Furthermore, the use of topical corticosteroids for the treatment of uncontrolled flares in adults, children and infants was lower in the pimecrolimus groups than in the vehicle groups.

Topical pimecrolimus 1.0% cream is well tolerated in atopic dermatitis patients of all age groups. There were no clinically relevant systemic adverse events reported from any of the studies in patients with atopic dermatitis. The most frequently reported adverse events pertained to application site reactions, such as burning and a feeling of warmth.

In conclusion, topical pimecrolimus 1.0% cream has shown efficacy in the treatment of mild to moderate atopic dermatitis in infants, children and adults. Although tolerability data concerning infants and children have not yet been published in full, the drug appears to be well tolerated in all age groups, and there have been no reports of clinically relevant systemic adverse events. Furthermore, pimecrolimus 1.0% cream has shown no potential for skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Pimecrolimus 1.0% cream provides a promising and well tolerated treatment option in the management of infants, children and adults with mild to moderate atopic dermatitis.

Pharmacodynamic Properties

Pimecrolimus binds to macrophilin-12 (FKBP12) at nanomolar concentrations (concentration required for 50% inhibition =1.8 nmol/L), and the resulting complex inhibits calcineurin, causing a signal transduction blockade in target cells. As a consequence, the synthesis of inflammatory cytokines is blocked at the level of gene transcription. The release of T helper (Th)-1 and Th2 cytokines from a house dust mite-sensitive Thcell clone was inhibited by pimecrolimus 0.2 to 0.42 nmol/L.

Pimecrolimus dose-dependently inhibited the anti-immunoglobulin Einduced release of the preformed pro-inflammatory mediators histamine and tryptase from activated human dermal mast cells, and β-hexosaminidase, serotonin and tumour necrosis factor-α from activated rat basophilic leukaemia 2H3 cells. Furthermore, the up-regulation of co-receptors CD134 and CD137, which are implicated in the activation and expansion of inflammatory effector T cells, was dose-dependently inhibited by pimecrolimus (80% inhibition at 10 nmol/L in primary T cells).

Twice-daily topical pimecrolimus 1.0% showed no potential for skin atrophy when applied for 6 days/week to normal skin in a randomised, double-blind, vehicle-controlled 4-week study in 16 healthy volunteers. Conversely, betamethasone-17-valerate 0.1% and triamcinolone acetonide 0.1% creams significantly reduced skin thickness (by 7.9 and 12.2%, respectively) compared with baseline thickness.

Symptoms of nickel-induced allergic contact dermatitis in 66 healthy volunteers were significantly reduced by twice-daily topical pimecrolimus 0.6% for 12 days compared with vehicle. Furthermore, after 12 days, there was no significant between-group difference in mean reductions of the total symptom score for erythema, induration and vesiculation in patients treated twice daily with topical pimecrolimus 0.6% or betamethasone-17-valerate 0.1% (32% reduction for both).

Pharmacokinetic Profile

Systemic absorption of topically applied pimecrolimus 1.0% has been investigated in short-term (3 weeks) and long-term (up to 12 months) studies in a total of 52 adults and 58 children (aged ≥3 months) with moderate to severe atopic dermatitis. In all these studies, blood concentrations of pimecrolimus were consistently low, regardless of the extent of lesions treated (up to 92% body surface area involved) or duration of therapy. No systemic accumulation was observed over the treatment period.

In 12 adult patients with moderate to severe atopic dermatitis, blood concentrations of pimecrolimus during 3 weeks of twice daily treatment with topical pimecrolimus 1.0% were ≤1.4 μg/L [78% of the concentrations were below the assay limit of quantification (LoQ)]. The area under the whole-blood concentration-time curve from 0 to 12 hours ranged from <0.5 to 11.4 μ · h/L.

In 40 adult patients with extensive atopic dermatitis (up to 62% body surface area affected) treated with pimecrolimus cream 1.0% for 1 year, 98% of the blood samples collected provided concentrations below the assay LoQ; the maximum concentration measured was 0.8 μg/L.

In 58 patients aged 3 months to 14 years with moderate to severe atopic dermatitis (10 to 92% affected body surface area) treated with pimecrolimus 1.0% twice daily for 3 weeks, 93% of the blood concentrations of pimecrolimus were <2 μg/L. The concentrations were in a range similar to those measured in adult patients.

In a study examining the pharmacokinetics of single-dose oral pimecrolimus, healthy volunteers received 5, 15, 30 or 60mg under fasting conditions. The fall in concentrations after maximum plasma concentrations had been reached involved three disposition phases with an apparent terminal elimination half-life of 30 to 40 hours. The mean apparent systemic clearance among the pimecrolimus 30 and 60mg groups was 71 and 91 L/h, and the apparent volume of distribution was 3452 and 4830L, respectively. Proportionality between the dose of the drug and maximum concentrations of pimecrolimus was observed.

Pimecrolimus is stable in the skin but, when taken up into the circulation, it is metabolised by the liver cytochrome P450 3A4 pathway and excreted in the faeces, as shown after oral administration.

Therapeutic Efficacy

Topical pimecrolimus 1.0% has been evaluated in randomised, double-blind, vehicle-controlled clinical trials in infants (aged 3 to 23 months), children (aged 2 to 17 years) and adults with mild to severe atopic dermatitis (the majority of patients had moderate disease). In clinical trials, the dosage of topical pimecrolimus was 1.0% administered twice daily as a cream unless otherwise stated.

In Adults: Twice daily administration of pimecrolimus 1.0% cream for 3 weeks was significantly more effective than once daily administration or vehicle at reducing symptoms of atopic dermatitis, as measured by the Atopic Dermatitis Severity Index (ADSI), in 34 patients with disease of mild to moderate severity. The group that received pimecrolimus twice daily showed a 71.9% mean reduction in the ADSI score at endpoint, compared with a mean reduction of 10.3% at the vehicle-treated sites. Furthermore, pimecrolimus demonstrated a significant therapeutic effect by day 2 compared with vehicle (a reduction in the ADSI score of 18.5% compared with a 1.5% increase, respectively). At sites treated with pimecrolimus once daily, the mean percentage reduction from baseline in the ADSI total score was 37.7%, compared with 6.2% at sites treated with vehicle.

In a dose-finding study involving 260 patients, pimecrolimus 0.2,0.6 and 1.0% creams were significantly more effective than vehicle at reducing total Eczema Area and Severity Index (EASI) scores after 3 weeks of twice daily treatment. Among patients randomised to pimecrolimus 1.0%, the median reduction from baseline in EASI scores was 47%, compared with a 0% reduction among vehicle recipients. Pimecrolimus 0.6 and 1.0% were also associated with significant improvements in pruritus compared with vehicle; at endpoint, the proportion of patients with absent or mild pruritus increased to 52.4 from 11.9% at baseline and to 46.7 from 6.7% at baseline for pimecrolimus 0.6 and 1.0%, respectively. In comparison, absent or mild pruritus was present in 18.6 and 4.7% of vehicle recipients at endpoint and baseline, respectively.

In a study in 192 adults with mild to moderate atopic dermatitis, topical pimecrolimus 1.0% significantly reduced the incidence of eczematous flares and the need for rescue treatment with topical corticosteroids compared with vehicle. Among patients in the pimecrolimus group, 14.8% were treated with topical corticosteroids, compared with 37.3% of patients in the vehicle group. The mean number of disease flares in patients who received pimecrolimus was 1.2, compared with 2.6 in patients who received vehicle. Reductions in total EASI scores and the severity of pruritus were also significantly in favour of pimecrolimus.

In Infants aged 3 to 23 Months: In a study involving 186 infants with mild to moderate atopic dermatitis, treatment with pimecrolimus 1.0% cream for up to 6 weeks resulted in a significant reduction in EASI and Investigators Global Assessment (IGA) scores, as well as in the severity of pruritus.

Compared with a conventional therapy, pimecrolimus 1.0% cream significantly educed the incidence of eczematous flares in the first 6 months of a 1 -year tudy involving 251 infants with mild to very severe atopic dermatitis (the majority f patients had moderate disease). 70% of patients in the pimecrolimus group completed 6 months of treatment without experiencing a flare, compared with 33% of patients in the control group. The mean number of days that patients n the control group were treated with corticosteroids (all patients were able to eceive emollients for skin care and medium potency corticosteroids for eczematous lares not controlled by study medication) was approximately twice as high as that in the pimecrolimus group.

In children aged 2 to 17 years. Combined results from two studies showed hat pimecrolimus 1.0% cream was significantly more effective than vehicle at educing symptoms of the disease in 403 children with mild to moderate atopic ermatitis. After 6 weeks, the median reduction of the EASI total score was 59% n the pimecrolimus group, compared with 14% in the vehicle group. Treatment with pimecrolimus was also associated with a significant improvement in healthrelated uality-of-life scores based on a 28-point questionnaire filled out by the patients’ parents.

Compared with a conventional therapy, pimecrolimus 1.0% cream significantly educed the incidence of eczematous flares in the first 6 months of a year-long study involving 713 patients with predominantly moderate atopic dermatitis. At month 6, 60% of patients in the pimecrolimus group remained free of flares, compared with 35% in the conventional therapy control group. Over the course of the year, fewer patients in the pimecrolimus group than patients in the control group were treated with corticosteroids (57 vs 32).

Tolerability

Evidence to date indicates that topical pimecrolimus 1.0% is well tolerated in patients of all age groups (infants aged 3 to 23 months, children aged 2 to 17 years and adults) with atopic dermatitis.

The most frequently reported adverse events during treatment with pimecrolimus 1.0% cream were application site reactions, such as burning and a feeling of warmth, which occurred in approximately 10% of patients aged 2 to 17 years, and in about 26% of adults.

There were no significant between-group differences in the incidence of adverse events among 192 adult patients with moderate to severe atopic dermatitis who received pimecrolimus 1.0% or vehicle twice daily according to need for up to 1 year.

There are limited published data on the tolerability of pimecrolimus 1.0% in infants and children because the five clinical trials have, so far, been reported only as abstracts. However, there were no reports of clinically relevant systemic adverse events. The incidence of skin infections in 335 patients aged 2 to 17 years treated with pimecrolimus 1.0% cream was low (≈5%).

Dosage and Administration

Pimecrolimus 1.0% has been approved in the US for the short-term and intermittent long-term treatment of mild to moderate atopic dermatitis in non-immunocompromised patients aged ≥2 years who do not respond well to, or may have adverse effects with, conventional treatments.

Pimecrolimus 1.0% cream is applied twice daily to all affected skin areas as a thin layer and rubbed in gently and completely. The drug should be used as long as signs and symptoms persist. If disease resolution occurs, treatment should be stopped; if symptoms persist beyond 6 weeks, the patient should be re-evaluated.

A change in dosage is not required in patients with renal or hepatic insufficiency. Pimecrolimus should not be applied to areas of active cutaneous viral infection. Furthermore, because pimecrolimus may be associated with an increased risk of varicella zoster virus infection, herpes simplex virus infection or eczema herpeticum, the use of the drug in the presence of these infections is cautioned.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Keri Wellington & Blair Jarvis

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  1. Keri Wellington
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  2. Blair Jarvis
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Correspondence to Keri Wellington.

Additional information

Various sections of the manuscript reviewed by: B.R. Allen, Department of Dermatology, Queen’s Medical Centre, Nottingham, England; J. Berth-Jones, Department of Dermatology, Walsgrave Hospital, Walsgrave, Coventry, England; J.D. Bos, Academic Medical Centre, Department of Dermatology, Universiteit van Amsterdam, Amsterdam, The Netherlands; A. Gottlieb, Department of Medicine and Clinical Research Center, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA; K. Landow, University of Southern California School of Medicine, Los Angeles, California, USA; A.M. Oakley, Tristram Clinic, Hamilton, New Zealand; A.S. Paller, Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, USA; S. Reitamo, Department of Dermatology, Hospital for Skin and Allergic Diseases, Helsinki University Central Hospital, Helsinki, Finland; A.K. Silverman, Dallas, Texas, USA.

Data Selection

Data Selection Sources: Medical literature published in any language since 1980 on pimecrolimus, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘SDZ-ASM-981’. EMBASE search terms were ‘ASM 981’ or ‘SDZ ASM 981’. AdisBase search terms were ‘pimecrolimus’ or ‘ASM 981’ or ‘SDZ ASM 981’. Searches were last updated 12 Feb 2002.

Selection: Studies in patients with atopic dermatitis who received topical pimecrolimus. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Pimecrolimus, SDZ ASM 981, ASM 981, atopic dermatitis, atopic eczema, pharmacodynamics, pharmacokinetics, therapeutic use.

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Wellington, K., Jarvis, B. Topical Pimecrolimus. Drugs 62, 817–840 (2002). https://doi.org/10.2165/00003495-200262050-00007

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