Chemical formula: C₄₃H₆₈ClNO₁₁ Molecular mass: 810.46 g/mol PubChem compound: 6509979
Pimecrolimus is a lipophilic anti-inflammatory ascomycin macrolactam derivative and a cell selective inhibitor of the production and release of pro-inflammatory cytokines.
Pimecrolimus binds with high affinity to macrophilin-12 and inhibits the calcium-dependent phosphatase calcineurin. As a consequence, it blocks the synthesis of inflammatory cytokines in T cells.
Pimecrolimus exhibits high anti-inflammatory activity in animal models of skin inflammation after topical and systemic application. In the pig model of allergic contact dermatitis, topical pimecrolimus is as effective as potent corticosteroids. Unlike corticosteroids, pimecrolimus does not cause skin atrophy in pigs and does not affect Langerhans´cells in murine skin.
Pimecrolimus neither impairs the primary immune response nor affects lymph nodes in murine allergic contact dermatitis. Topical pimecrolimus penetrates similarly into, but permeates much less through human skin than corticosteroids, indicating a very low potential of pimecrolimus for systemic absorption.
In conclusion, pimecrolimus has a skin-selective pharmacological profile different from corticosteroids.
The bioavailability of pimecrolimus in mini-pigs following a single dermal dose (applied for 22h under semi-occlusion) was 0.03%. The amount of active substance-related material in the skin at the application site (almost exclusively unchanged pimecrolimus) remained practically constant for 10 days.
Systemic exposure to pimecrolimus was investigated in 12 adults with atopic dermatitis who were treated with pimecrolimus twice daily for 3 weeks. The affected body surface area (BSA) ranged from 15-59%. 77.5% of pimecrolimus blood concentrations were below 0.5 ng/ml and 99.8% of the total samples were below 1 ng/ml. The highest pimecrolimus blood concentration was 1.4 ng/ml in one patient.
In 40 adult patients treated for up to 1 year with pimecrolimus, having 14-62% of their BSA affected at baseline, 98% of pimecrolimus blood concentrations were below 0.5 ng/ml. A maximum blood concentration of 0.8 ng/ml was measured in only 2 patients in week 6 of treatment. There was no increase in blood concentration over time in any patient during the 12 months of treatment. In 8 adult atopic dermatitis patients, in which AUC levels could be quantified, the AUC(0-12h) values ranged from 2.5 to 11.4 ng h/ml.
Systemic exposure to pimecrolimus was investigated in 58 paediatric patients aged 3 months to 14 years. The affected BSA ranged from 10-92%. These children were treated with pimecrolimus twice daily for 3 weeks and five out of them were treated for up to 1 year on a “as needed” basis.
Pimecrolimus blood concentrations were consistently low regardless of the extent of lesions treated or duration of therapy. They were in a range similar to that measured in adult patients. Around 60% of pimecrolimus blood concentrations were below 0.5 ng/ml and 97% of all samples were below 2 ng/ml. The highest blood concentrations measured in 2 paediatric patients aged 8 months to 14 years were 2.0 ng/ml.
In infants (aged 3 to 23 months), the highest blood concentration measured in one patient was 2.6 ng/ml. In the 5 children treated for 1 year, blood concentrations were consistently low (maximum blood concentration was 1.94 ng/ml in 1 patient). There was no increase in blood concentration over time in any patient during the 12 months of treatment.
In 8 paediatric patients aged 2-14 years, AUC(0-12h) ranged from 5.4 to 18.8 ng h/ml. AUC ranges observed in patients with <40% BSA affected at baseline were comparable to those in patients with ≥40% BSA.
The maximum body surface area treated was 92% in clinical pharmacology studies and up to 100% in Phase III trials.
Consistent with its skin selectivity, after topical application, pimecrolimus blood levels are very low. Therefore pimecrolimus metabolism could not be determined after topical administration.
In vitro plasma protein binding studies have shown that 99.6% of pimecrolimus in plasma is bound to proteins. The major fraction of pimecrolimus in plasma is bound to different lipoproteins.
After single oral administration of radiolabeled pimecrolimus in healthy subjects, unchanged pimecrolimus was the major active substance-related component in blood and there were numerous minor metabolites of moderate polarity that appeared to be products of O-demethylations and oxygenation.
No metabolism of pimecrolimus was observed in human skin in vitro.
Active substance-related radioactivity was excreted principally via the faeces (78.4%) and only a small fraction (2.5%) was recovered in urine. Total mean recovery of radioactivity was 80.9%. Parent compound was not detected in urine and less than 1% of radioactivity in faeces was accounted for by unchanged pimecrolimus.
Conventional studies of repeated dose toxicity, reproductive toxicity and carcinogenicity using oral administration produced effects at exposures sufficiently in excess of those in man to be of negligible clinical significance. Pimecrolimus had no genotoxic, antigenic, phototoxic, photoallergenic or photocarcinogenic potential. Dermal application in embryo/fetal developmental studies in rats and rabbits and in carcinogenicity studies in mice and rats were negative.
Effects on reproductive organs and altered sex hormone functions were seen in male and female rats in repeated dose toxicity studies after oral administration of 10 or 40 mg/kg/day (=20 to 60 times the maximum human exposure after dermal application). This is reflected by the findings from the fertility study. The No Observed Adverse Effect Level (NOAEL) for female fertility was 10 mg/kg/day (=20 times the maximum human exposure after dermal application). In the oral embryotoxicity study in rabbits, a higher resorption rate associated with maternal toxicity was observed at 20 mg/kg/day (=7 times the maximum human exposure after dermal application); the mean number of live fetuses was not affected.
Dose-dependent increases in the incidence of lymphomas were observed at all doses in a 39 week monkey oral toxicity study. Signs of recovery and/or at least partial reversibility of the effects were noted upon cessation of dosages in a few animals. Failure to derive a NOAEL precludes an assessment of the margin of safety between a non-carcinogenic concentration in the monkey and exposures in patients. The systemic exposure at the LOAEL of 15mg/kg/day was 31 times the highest maximum exposure observed in a human (paediatric patient). The risk for humans cannot be completely ruled out as the potential for local immunosuppression with the long-term use of pimecrolimus cream is unknown.
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