Topical Pimecrolimus

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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. 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). 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 vs 32). 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%). 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.