Biomed Tech 2013; 58 (Suppl. 1) © 2013 by Walter de Gruyter · Berlin · Boston. DOI 10.1515/bmt-2013-4133
Certified dOFM sampling devices provide access to target tissue in pharmaceutical trials M.Bodenlenz1, C.Dragatin1, C.Hoefferer1, T.Birngruber1, J.Priedl1, F.Feichtner1, R.Schaller1, B.Aigner2, S.Korsatko2, T.R.Pieber1,2 and F.Sinner1,2 1
HEALTH—Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria 2 Dept. of Internal Medicine, Division of Endocrinology and Metabolism, Medical University Graz, Graz, Austria
[email protected] Abstract: Clinical testing of dermatological drugs requires access to the site of drug action within the dermis. Conventional methods such as skin biopsies are rather invasive and provide limited data on the kinetics and dynamics of drugs. We present minimally invasive dermal sampling probes and a wearable pump for continuous sampling from the dermis. These dermal open flow microperfusion (dOFM) devices comply with international medical device guidelines (CE certified) and have demonstrated applicability and tolerability in clinical trials. dOFM is likely to become an invaluable tool for clinical bioequivalence trials prior to market release of generic drugs.
system comprises a dermal probe, a wearable pump, a sample collection unit as well as several aids to facilitate standardized application. The devices fully comply with current medical device guidelines and recently received certification (CE label).
Keywords: open flow microperfusion, medical devices, wearable multichannel pump, human trials, preclinical trials
Introduction Traditionally, decisions in medical practice and in drug development are based on concentrations of endogenous and exogenous molecules measured in the blood. However, the blood levels of most dermatological drugs have little relevance, because the biochemical and pharmacological events take place in the dermis and epidermis. In studies on dermatological drugs, skin biopsies are taken but are not well tolerated by patients because the technique is invasive. Repetitive biopsies are thus not possible, and pharmacokinetic and pharmacodynamic data from the target organ cannot be studied adequately. Consequently, less invasive techniques, such as dermal microdialysis (MD), have been developed for continuous sampling of drugs and biomolecules [1]. However, MD has limitations in size and lipophilicity of drugs and biomarkers that can be sampled. We aimed to develop novel devices with extended sampling capacity for pharmaceutical and medical research.
Methods The principle of open-flow microperfusion (OFM) [2] was adapted for application within the dermal layer of the skin, thus forming dermal OFM (dOFM). The sampling
Fig. 1: Schematic of a dOFM sampling system. The dOFM probe is inserted into the dermis and continuously perfused at µL rates, providing samples for subsequent laboratory analysis. In- and outflow are controlled using the OFM pump. The dOFM probe is sterile class IIa product, and can be introduced into the dermis by using a thin needle. The probe’s mesh-like sampling section enables direct access to dermal interstitial fluid with all its constituents for subsequent assay (Fig. 2). The OFM pump is wearable and operates 3 to 6 probes of (MD&OFM) in various perfusion modes (push, pull, push-pull). Its six peristaltic pump channels can deliver flow rates of 0.1-10 µL min for >48 h. Single-use components (sterile tubing kit, perfusate bag, waste bag) are sterile, which means the pump is also a class IIa product (Fig.3). The sample collection unit acts as a sample trap between probe and pump. Conventional vials or glass capillaries can be used, so that biological samples can be collected with minimum delay and negligible risk of adsorption. Supporting equipment (skin-stabilization ring, stencil) stabilize the investigated skin area for the duration of the
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study and enable reproducible application of probes and study drug.
Fig. 2: dOFM probe with a mesh-like exchange area (OD 0.32mm). The probe is CE-labelled class IIa.
Fig. 3: Wearable OFM pump: 0.1-10 µL/min, 6 peristaltic channels, push and pull, 10 ml perfusate and waste bags, sterile fluidic kits (left), CE-labelled class IIa.
Results The medical device trial demonstrated applicability, tolerability and reproducible performance of the dOFM devices. Most importantly, (i) the 17 volunteers rated the insertion pain as acceptable, (ii) the physicians were able to place the probes reproducibly within the dermis, and (iii) the devices enabled continuous sampling over 25h with low variation of the recovered analyte (CV12 h studies, and that this model enables set-ups with a multitude of topical test sites for direct comparisons of topical formulations.
Discussion Our data demonstrate that dOFM devices are safe, tolerable and provide access to virtually all molecules of interest at the target-tissue level in humans and animals. dOFM overcomes significant limitations of state of the art methods and, therefore, should become a valuable tool for the study of skin-barrier function, topical formulations and new classes of biological drugs. Moreover, these devices may facilitate the comparison of generic drugs to reference products in bioequivalence trials.
Acknowledgement The authors thank the Federal Ministry of Economy, Family and Youth for funding the design of the medical devices through its program ‘Research Studios Austria’. Fig. 4: Dermal OFM devices (12 probes, 4 pumps) in a clinical trial. The volunteer is mobile while allowing continuous sampling of dermal fluid for >24 h. In an initial medical device trial we evaluated the applicability, tolerability and reproducibility of the devices over >24 h in 17 healthy and psoriatic volunteers. In this trial, we used up to 9 probes per subject and focused on basic parameters such as application time, pain perception, reproducibility of implantation depths, usability, hourly sample volumes, relative recovery and its drift and variation. In subsequent pharmaceutical trials in animals and in humans (Fig. 4) we evaluated the sampling capabilities of the dOFM probes with regard to the lipophilicity and molecular size of the investigated drugs and inflammation markers.
Bibliography [1] Chaurasia CS, Müller M, Bashaw ED, Benfeldt E et al. (2007) AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res. 24(5):1014-25 [2] Schaupp L, Ellmerer M, Brunner GA, Wutte A, Sendlhofer G, Trajanoski Z, Skrabal F, Pieber TR, Wach P (1999). Direct access to interstitial fluid in adipose tissue in humans by use of open-flow microperfusion. Am J Physiol. 276(2 Pt 1):E401-8 [3] M.Bodenlenz, B.Aigner, C.Dragatin, L.Liebenberger, S.Zahiragic, C.Höfferer, T. Birngruber, J.Priedl, F.Feichtner, L.Schaupp, S.Korsatko, M.Ratzer, C. Magnes, T.R.Pieber and F.Sinner. Clinical applicability of dOFM devices for dermal sampling. Skin Res Technol. 2013 Apr 13. doi: 10.1111/srt.12071. [Epub ahead of print]
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