Author's personal copy Research Paper Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling Manfred Bodenlenz a , Christian Höfferer a , Christoph Magnes a , Roland Schaller-Ammann a , Lukas Schaupp a,b , Franz Feichtner a , Maria Ratzer a , Karin Pickl a , Frank Sinner a,b , Andrea Wutte b , Stefan Korsatko b , Gerd Köhler b , Franz J. Legat c , Eva M. Benfeldt d , Andrew M. Wright e , Daniel Neddermann e , Thomas Jung e , Thomas R. Pieber a,b,⇑ a HEALTH – Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., Graz, Austria b Division of Endocrinology and Metabolism, Dept. of Internal Medicine, Medical University of Graz, Austria c Research Unit for Photodermatology, Dept. of Dermatology, Medical University of Graz, Austria d Dept. of Dermatology, University of Copenhagen, Roskilde Sygehus, Denmark e Novartis Pharma AG, Basel, Switzerland article info Article history: Received 13 August 2011 Accepted in revised form 16 April 2012 Available online 24 April 2012 Keywords: Open-flow microperfusion Psoriasis Topical drugs Skin penetration Pharmacokinetics Pharmacodynamics abstract Background: Methodologies for continuous sampling of lipophilic drugs and high-molecular solutes in the dermis are currently lacking. We investigated the feasibility of sampling a lipophilic topical drug and the locally released biomarker in the dermis of non-lesional and lesional skin of psoriatic patients over 25 h by means of membrane-free dermal open-flow microperfusion probes (dOFM) and novel wear- able multi-channel pumps. Methods: Nine psoriatic patients received a topical p-38 inhibitor (BCT194, 0.5% cream) on a lesional and a non-lesional application site once daily for 8 days. Multiple dOFM sampling was performed for 25 h from each site on day 1 and day 8. Patients were mobile as dOFM probes were operated by a novel light-weight push–pull pump. Ultrasound was used to verify intradermal probe placement, cap-LC– MS/MS for BCT194 and ELISA for TNFa analysis. Results: dOFM was well tolerated and demonstrated significant drug concentrations in lesional as well as non-lesional skin after 8 days, but did not show significant differences between tissues. On day 8, TNFa release following probe insertion was significantly reduced compared to day 1. Conclusions: Novel membrane-free probes and wearable multi-channel pumps allowed prolonged intra- dermal PK/PD profiling of a lipophilic topical drug in psoriatic patients. This initial study shows that dOFM overcomes limitations of microdialysis sampling methodology, and it demonstrates the potential for PK/PD studies of topical products and formulations in a clinical setting. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction A critical stage in the development of topical drugs is the provi- sion of evidence for effective penetration of the skin’s barrier layer, the stratum corneum, and evidence for the efficacy at the intended target site of action, the dermis, in clinical trials [1–3]. Traditional methods in skin research such as punch or shave biopsies, suction blister [4] and tape stripping [5,6] provide limited kinetic informa- tion [1,7]. Furthermore, biopsies and blisters are too invasive for multiple or repetitive application in volunteers, and tape stripping does not provide information from the dermis being the site of action. Progress was made with the introduction of the minimally invasive, tissue-specific continuous approach of microdialysis (MD) [8,9] into dermatological research in 1991 [10] and then with the comprehensive evaluation of dermal microdialysis (DMD) for topical drug sampling [11,12]. MD proved to be a versatile, safe and valuable tool for pharmacokinetic (PK) and pharmacodynamic (PD) studies [7]. Hence, MD and DMD have also gained attention as tools for drug testing by authorities [1,3]. However, MD has some limitations when sampling lipophilic, protein-bound and high-molecular drugs [1,7,13–17]. Due to non-specific membrane binding and size exclusion, these com- pound classes show low or no recovery in MD. These shortcomings particularly affect research on the PK/PD of anti-inflammatory drugs for topical treatment of skin disease. These topical drugs are designed as lipophilic entities to provide skin-selectivity [18,19], and the associated markers (cytokines) are of high 0939-6411/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejpb.2012.04.009 ⇑ Corresponding author. HEALTH – Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., Elisabethstraße 5, A-8010 Graz, Austria. Tel.: +43 316 876 4001; fax: +43 316 876 4010. E-mail address: thomas.pieber@joanneum.at (T.R. Pieber). European Journal of Pharmaceutics and Biopharmaceutics 81 (2012) 635–641 Contents lists available at SciVerse ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb