Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies
Autor: | Maja Lambert, Stefan Eirefelt, Simon Feldbaek Nielsen, Malene Bertelsen, Jens Christian Højland Larsen, Thomas Birngruber, Frank Sinner, Fredrik Johansson, Joanna Hummer, Line Hollesen Basse |
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Rok vydání: | 2020 |
Předmět: |
Keratinocytes
Pyridines Biopsy Drug Compounding Microdialysis Skin Absorption Pharmaceutical Science Human skin 02 engineering and technology Pharmacology Administration Cutaneous 030226 pharmacology & pharmacy Dermatitis Atopic 03 medical and health sciences Clinical Trials Phase II as Topic 0302 clinical medicine Drug Stability Pharmacokinetics Interstitial fluid Acetamides Cyclic AMP Humans Medicine Pharmacology (medical) PDE4 Inhibitors Cells Cultured Skin integumentary system medicine.diagnostic_test business.industry Organic Chemistry Extracellular Fluid 021001 nanoscience & nanotechnology Open flow Therapeutic Equivalency Pharmacodynamics Skin biopsy Molecular Medicine Biomarker (medicine) Phosphodiesterase 4 Inhibitors 0210 nano-technology business Biotechnology |
Zdroj: | Pharmaceutical Research. 37 |
ISSN: | 1573-904X 0724-8741 |
Popis: | To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement. Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7–33-fold higher than the dISF concentrations. Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution. |
Databáze: | OpenAIRE |
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