Novel catheters for in vivo research and pharmaceutical trials providing direct access to extracellular space of target tissues

Abstract

Medical and pharmaceutical research frequently requires direct access to the site of action of drugs and the withdrawal of tissue samples rather than withdrawal of blood samples. As alternative to invasive biopsy procedures less invasive continuous sampling techniques such as Microdialysis (μD) and Open-Flow Microperfusion (OFM) have been developed since the 1970ties. While μD-catheters recover substances through semi-permeable membranes OFM-catheters are membrane-free and thus permeable for all substances of interest at tissue level. We aimed at utilizing the advantages of the OFM principle and to develop catheters suitable for intradermal insertion to facilitate research in dermatology. Moreover, we aimed at demonstrating the feasibility of sampling lipophilic drugs from the dermis of patients in a clinical trial.Following development a trial was performed in 12 psoriatic patients. Lesional and non-lesional skin sites were treated for 8 days with a topical lipophilic immunoactive drug. Six catheters were implanted and OFM performed pre-dose and 24hrs post-dose on day 1 and day 8 for assessment of drug (by cap-LS-MS/MS) and according cytokine levels (TNFα, by ELISA). As reference for drug levels standard skin biopsies were taken at 4hrs post-dose.Dermal OFM was able to recover the lipophilic drug and TNFα and to provide 24hrs profiles of drug kinetics and action. Calculated AUC0 − 24 showed significant higher drug levels on day 8. In contrast, the skin biopsy procedure could not demonstrate any drug accumulation. Moreover, OFM profiles indicated a suppression of local TNFα release on day 8.We conclude that OFM can overcome limitations of state of the art methods and thus represents an alternative for basic research, the assessment of skin barrier function and drug penetration from topically applied formulations. The successful trial also led to the development of advanced catheters at medical product quality available by mid 2010.