Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion
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RESEARCH PAPER
Evaluating Dermal Pharmacokinetics and Pharmacodymanic E f f e c t o f S o f t To p i c a l P D E 4 I n h i b i t o r s : O p e n F l o w Microperfusion and Skin Biopsies Stefan Eirefelt 1 & Joanna Hummer 2 & Line Hollesen Basse 3 & Malene Bertelsen 1 & Fredrik Johansson 1 & Thomas Birngruber 2 & Frank Sinner 2 & Jens Larsen 1 & Simon Feldbæk Nielsen 1 & Maja Lambert 1 Received: 5 August 2020 / Accepted: 26 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. * Maja Lambert [email protected] 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
Present address: Discovery & Development PKPD, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark
KEY WORDS cAMP . open flow microperfusion . PDE4 inhibitors . skin PK/PD . topical drug delivery
ABBREVIATIONS AD cAMP dISF dOFM HSA MD PDE4 PK/PD
Atopic dermatitis Cyclic adenosine monophosphate Dermal interstitial fluid concentration Dermal open flow microperfusion Human serum albumin Microdialysis Phosphodiesterase 4 Pharmacokinetic / Pharmacodynamic
INTRODUCTION Atopic Dermatitis (AD) is one of the most common skin diseases with a prevalence of 15–30% in children and 2–10% in adults in Western European countries and North America and a steady increase in developing countries (1). AD is a chronic inflammatory skin disease and is characterized by eczematous skin plaques, dry skin and intense pruritus (2). The standard treatments for AD are topical corticosteroids (3), calcineurin inhibitors, systemic immunosuppre
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