Pimecrolimus Identifies a Common Genomic Anti-inflammatory Profile, is Clinically Highly Effective in Psoriasis and is Well Tolerated

Abstract

The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release inhibitor that so far has not been administered systemically to humans. In this phase I/II randomized double-blind, placebo-controlled, multiple rising dose proof of concept study psoriasis patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation but no changes in gene expression linked to drug-related side-effects. A steady state of pimecrolimus was reached after 5-10 d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per ml, respectively, at steady state at the highest dose. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%, respectively. Histopatho logically and immunopathologically there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. We conclude that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated and this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases.

Toxicogenomics in Drug Development

“…Gene expression profiling of blood cells of individuals during therapy identified a common genomic profile with a downregulation of genes associated with the known target pathway of pimecrolimus, inflammation, proliferation, chemotaxis, and migration of leukocytes, but no changes in gene expression that might be linked to treatment-related immunosuppression and toxicity. This expression profile was highly consistent with the observed clinical efficacy and tolerability of pimecrolimus, allowing the authors to conclude that pimecrilimus taken orally is highly effective on patients with psoriasis and well tolerated (60). In addition, the gene expression findings from this study suggest that pimecrolimus has unique anti-inflammatory qualities that may be effective for other inflammatory skin diseases.…”

“…Due to the novelty of toxicogenomics as a tool in drug development, to date, there are few published studies showing the applicability of gene expression profiling in clinical trials. Recently, however, gene expression profiling was incorporated into a proof of concept phase I/II study in which the efficacy, safety and tolerability of orally administered pimecrolimus was evaluated in psoriasis patients (60). Gene expression profiling of blood cells of individuals during therapy identified a common genomic profile with a downregulation of genes associated with the known target pathway of pimecrolimus, inflammation, proliferation, chemotaxis, and migration of leukocytes, but no changes in gene expression that might be linked to treatment-related immunosuppression and toxicity.…”

Safety and Tolerability of 1% Pimecrolimus Cream Among Infants: Experience With 1133 Patients Treated for Up to 2 Years

“…30 Overall, the results of pharmacokinetic studies among infants indicate that treatment with 1% pimecrolimus cream leads to minimal systemic exposure, even for patients with extensive disease, and that pimecrolimus blood concentrations remain low during treatment for up to 1 year. The highest concentration measured (2.6 ng/mL) was well below the mean peak concentration (54 ng/mL) detected among adult psoriatic patients treated for 28 days with 30 mg of pimecrolimus administered orally twice daily, 46 a dose that was well tolerated. 46 In line with these findings, no clinically relevant systemic adverse events were reported for the infants enrolled in the pharmacokinetic studies.…”

“…The highest concentration measured (2.6 ng/mL) was well below the mean peak concentration (54 ng/mL) detected among adult psoriatic patients treated for 28 days with 30 mg of pimecrolimus administered orally twice daily, 46 a dose that was well tolerated. 46 In line with these findings, no clinically relevant systemic adverse events were reported for the infants enrolled in the pharmacokinetic studies. 30,44 …”

“…Among human subjects, no manifestations of toxicity were observed among adult psoriatic patients treated with orally administered pimecrolimus for up to 12 weeks, at doses associated with mean peak blood concentrations of 54 ng/mL. [42][43][44][45][46] Systemic exposure to pimecrolimus during treatment with 1% pimecrolimus cream was assessed in pharmacokinetic studies by measuring pimecrolimus blood concentrations at various times during the treatment period. A summary of the pharmacokinetic studies completed among pediatric patients with AD is reported in Table 1.…”