AimsTo compare the time profile of insulin detemir and human insulin concentrations in the interstitial fluid (ISF) of subcutaneous adipose tissue during constant i.v. infusion and to investigate the relationship between the pharmacokinetics of both insulin molecules in plasma and the ISF of subcutaneous adipose tissue.MethodsDuring a 6-h hyperinsulinaemic-euglycaemic clamp (plasma glucose level 8mmol/l) human insulin (21 and 42pmol/min/kg) or insulin detemir (209 and 417pmol/min/kg) were infused i.v. in eight rats per dose level. Open flow microperfusion (OFM) was used to continuously assess interstitial insulin concentrations in subcutaneous adipose tissue.ResultsAt the lower infusion rate, insulin detemir appeared significantly later in the ISF than in the plasma (p<0.05) and also appeared later in the ISF relative to human insulin (p<0.005).ConclusionsBy using OFM we were able to monitor albumin-bound insulin detemir directly in the ISF of subcutaneous tissue and confirm its delayed transendothelial passage to a peripheral site of action.

BackgroundSampling the dermal interstitial fluid (ISF) allows the pharmacokinetics and pharmacodynamics of dermatological drugs to be studied directly at their site of action. Dermal open-flow microperfusion (dOFM) is a recently developed technique that can provide minimally invasive, continuous, membrane-free (thus unfiltered) access to the dermal ISF. Herein, we evaluate the clinical applicability and reliability of novel wearable dOFM devices in a clinical setting.MethodsPhysicians inserted 141 membrane-free dOFM probes into the dermis of 17 healthy and psoriatic volunteers and sampled dermal ISF for 25h by using wearable push-pull pumps. The tolerability, applicability, reproducibility, and reliability of multiple insertions and 25h continuous sampling was assessed by pain scoring, physician feedback, ultrasound probe depth measurements, and 25h-drift and variability of the sodium relative recovery.ResultsInsertion pain was moderate and decreased with each additional probe. Probe insertion was precise, although slightly deeper in lesional skin. The wearable push-pull pump enabled uninterrupted ISF sampling over 25h with low variability. The relative recovery was drift-free and highly reproducible.ConclusiondOFM sampling devices are tolerable and reliable for prolonged continuous dermal sampling in a multiprobe clinical setting. These devices should enable the study of a wide range of drugs and their biomarkers in the skin.

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.

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.