Stefan Eirefelt1, Joanna Hummer2, Line Hollesen Basse3, Malene Bertelsen1, Fredrik Johansson1, Thomas Birngruber2, Frank Sinner2, Jens Larsen1, Simon Feldbæk Nielsen1, Maja Lambert4. 1. LEO Pharma Global Research & Development, Industriparken 55, 2750, Ballerup, Denmark. 2. Joanneum Research Forschungsgesellschaft mbH, Health-Institute for Biomedicine and Health Sciences, Neue Stiftingtalstraße 2, 8010, Graz, Austria. 3. Discovery & Development PKPD, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark. 4. LEO Pharma Global Research & Development, Industriparken 55, 2750, Ballerup, Denmark. MLTDK@leo-pharma.com.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: To investigate the difference in clinical efficacy in ADpatients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 ADpatients 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.
Entities:
Keywords:
PDE4 inhibitors; cAMP; open flow microperfusion; skin PK/PD; topical drug delivery
Authors: Kurt Jarnagin; Sanjay Chanda; Dina Coronado; Vic Ciaravino; Lee T Zane; Emma Guttman-Yassky; Mark G Lebwohl Journal: J Drugs Dermatol Date: 2016-04 Impact factor: 2.114