Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients.

AIMS: To measure pimecrolimus blood concentrations and to evaluate tolerability and efficacy in children and infants treated topically for atopic dermatitis with pimecrolimus cream 1% for three weeks. METHODS: Three open label, non-controlled, multiple topical dose studies were conducted in children aged 8-14 years (study A, ten patients), and in infants aged 8-30 months (study B, eight patients) and 4-11 months (study C, eight patients). Pimecrolimus blood concentrations were determined on days 4 and 22 of treatment, and at end of study. Efficacy was assessed using the Eczema Area and Severity Index (EASI). RESULTS: Pimecrolimus blood concentrations were consistently low, typically (81%) below 1 ng/ml, with more than half of the measurements below the assay limit of quantitation (0.5 ng/ml) in studies A and B. The highest blood concentration measured throughout the three studies was 2.6 ng/ml. The cream was well tolerated, locally and systemically. The most common adverse event suspected to be related to study medication was a transient mild to moderate stinging sensation at the application site in 5/26 patients. There was no indication of any systemic adverse effect. The patients responded well to therapy with a rapid onset of action, usually within four days. Median reductions of EASI from baseline at day 22 were 55% (study A), 63% (study B), and 83% (study C). CONCLUSION: Three weeks treatment of children and infants with extensive atopic dermatitis, using pimecrolimus cream 1% twice daily, is well tolerated and results in minimal systemic exposure, at which no systemic effect is expected.

Use of human skin equivalent Apligraf for in vitro assessment of cumulative skin irritation potential of topical products.

The main goal of the present study was to investigate the response of the human skin equivalent Apligraf in vitro to the application of irritant substances and its predictivity as a screening tool for cumulative skin irritant potential in humans. Vaseline, calcipotriol, trans-retinoic acid, and sodium lauryl sulfate were applied to Apligraf in vitro for 24 h. Cell viability (lactate dehydrogenase leakage), release and mRNA expression of the proinflammatory cytokines IL-1alpha and IL-8, and morphological changes were assessed. The same products were applied to 30 healthy volunteers in a double-blind, randomized, vehicle-controlled within-subject study. The skin reactions after repeated 24-h applications over 3 weeks under Finn chamber patches were monitored by visual scoring and biophysical methods (trans-epidermal water loss, chromametry, and blood flow). Sodium lauryl sulfate was cytotoxic to Apligraf, and increased the release and expression of cytokines at low (0.2%, 0. 4%), but not at high (0.8%, 1%) concentrations. It induced severe irritancy in vivo. Trans-retinoic acid increased the expression and release of cytokines with no detectable cytotoxicity and showed moderate irritancy in humans. Although calcipotriol did neither affect cell viability nor the production of cytokines, it induced morphological signs of irritation and was mildly irritant for healthy volunteers. Vaseline was innocuous in vivo and induced no changes in Apligraf. In conclusion, the cumulative skin irritation potential of the tested products could be predicted with Apligraf in a sensitive and specific manner, by monitoring cytotoxicity, proinflammatory cytokines, and morphological changes.

Predictivity of an in vitro model for acute and chronic skin irritation (SkinEthic) applied to the testing of topical vehicles.

An in vitro human reconstructed epidermis model (SkinEthic) used for screening acute and chronic skin irritation potential was validated against in vivo data from skin tolerability studies. The irritation potential of sodium lauryl sulfate (SLS), calcipotriol and trans-retinoic acid was investigated. The in vitro epidermis-like model consists of cultures of keratinocytes from human foreskin on a polycarbonate filter. The modulation of cell viability, the release and gene expression of proinflammatory cytokines, interleukins 1alpha and 8, and morphological changes were evaluated during 3 days as endpoints representative for an inflammatory reaction. The cumulative irritation potential of the topical products was evaluated in a human clinical study by visual scoring and biophysical measurement of inflammatory skin reaction after repeated 24 h applications over 3 weeks under Finn chamber patches. All topical products that were nonirritating in the human study were noncytotoxic and did not induce cytokine expression in the in vitro acute model (day 1 exposure). All irritating controls exhibited specific cell viability and cytokine patterns, which were predictive of the in vivo human data. The ranking of mild to moderate skin irritation potential was based on the lack of cytotoxicity and the presence of cytokine patterns including gene expression specific for each irritant, using the chronic in vitro model (up to 3 days exposure). The human reconstructed epidermis model SkinEthic was shown to be a reliable preclinical tool predicting the irritation potential of topical products. Moreover, it is a useful model in a two-step tiered strategy for screening acute and chronic irritation potential for the selection of vehicles for new topical drugs.

Pharmacokinetic and pharmacodynamic data and models in clinical trials.

There is current emphasis for extended integration of pharmacokinetics (PK) and pharmacodynamics (PD) into all phases of new drug development, including large-scale clinical trials. In this paper, we focus on study design and data analysis issues for the investigation of pharmacokinetic/pharmacodynamic and blood level/effect relationships in patients. The application of descriptive and model-based regression statistical methodology for including sparse drug systemic concentration data in the analysis of efficacy and safety is illustrated by examples chosen from diverse therapeutic areas. The population approach, based on mixed-effects modelling, is one such methodology, which also provides new tools for analysis of response vs dose and response vs time data. The existence of a variety of statistical techniques for handling complex PK/PD time-varying data should increase the impact of such data analysis on future drug development.