Cutaneous pharmacokinetics-based bioequivalence: A clinical dermal open flow microperfusion verification study using lidocaine and prilocaine combination topical products.

Background: Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic drug products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established.

Comparative Study of Dermal Pharmacokinetics Between Topical Drugs Using Open Flow Microperfusion in a Pig Model.

Purpose: Accurate methods to determine dermal pharmacokinetics are important to increase the rate of clinical success in topical drug development. We investigated in an in vivo pig model whether the unbound drug concentration in the interstitial fluid as determined by dermal open flow microperfusion (dOFM) is a more reliable measure of dermal exposure compared to dermal biopsies for seven prescription or investigational drugs. In addition, we verified standard dOFM measurement using a recirculation approach and compared dosing frequencies (QD versus BID) and dose strengths (high versus low drug concentrations).

Characterizing Cutaneous Drug Delivery Using Open-Flow Microperfusion and Mass Spectrometry Imaging.

Traditionally, cutaneous drug delivery is studied by skin accumulation or skin permeation, while alternative techniques may enable the interactions between the drug and the skin to be studied in more detail. Time-resolved skin profiling for pharmacokinetic monitoring of two Janus Kinase (JAK) inhibitors, tofacitinib and LEO 37319A, was performed using dermal open-flow microperfusion (dOFM) for sampling of perfusate in an and setup in pig skin. Additionally, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed to investigate depth-resolved skin distributions at defined time points in human skin.

Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion.

Purpose: Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study.

Methods: Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.

LC/MS/MS analyses of open-flow microperfusion samples quantify eicosanoids in a rat model of skin inflammation.

Eicosanoids are lipid-mediator molecules with key roles in inflammatory skin diseases, such as psoriasis. Eicosanoids are released close to the source of inflammation, where they elicit local pleiotropic effects and dysregulations. Monitoring inflammatory mediators directly in skin lesions could provide new insights and therapeutic possibilities.

Quantification of acyclovir in dermal interstitial fluid and human serum by ultra-high-performance liquid-high-resolution tandem mass spectrometry for topical bioequivalence evaluation.

Time-concentration curves for the topical anti-viral drug acyclovir can provide valuable information for drug development. Open flow microperfusion is used for continuous sampling of dermal interstitial fluid but it requires validated methods for subsequent sample analysis. Therefore, we developed a sensitive, selective and high-throughput ultra-high-performance liquid chromatography-high-resolution tandem mass spectrometry method to determine acyclovir in human dermal interstitial fluid and serum.

Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence.

Background: The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products.

Objective: To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product.

β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis.

Background: IL-17A is a key driver of human autoimmune diseases, particularly psoriasis.

Objective: We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A-driven pathology.

Methods: We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti-IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin.

Kinetics of Clobetasol-17-Propionate in Psoriatic Lesional and Non-Lesional Skin Assessed by Dermal Open Flow Microperfusion with Time and Space Resolution.

Purpose: To evaluate the kinetics of topically applied clobetasol-17-propionate (CP-17) in lesional and non-lesional psoriatic skin when released from a commercially available low-strength cream using in vivo dermal open-flow microperfusion (dOFM).

Methods: Twelve patients received Dermovate® cream (CP-17, 0.05%) on small lesional and non-lesional skin test sites for 14 days, once daily.

Periodic extraction of interstitial fluid from the site of subcutaneous insulin infusion for the measurement of glucose: a novel single-port technique for the treatment of type 1 diabetes patients.

Background: Treatment of type 1 diabetes patients could be simplified if the site of subcutaneous insulin infusion could also be used for the measurement of glucose. This study aimed to assess the agreement between blood glucose concentrations and glucose levels in the interstitial fluid (ISF) that is extracted from the insulin infusion site during periodic short-term interruptions of continuous subcutaneous insulin infusion (CSII).

Subjects And Methods: A perforated cannula (24 gauge) was inserted into subcutaneous adipose tissue of C-peptide-negative type 1 diabetes subjects (n=13) and used alternately to infuse rapid-acting insulin (100 U/mL) and to extract ISF glucose during a fasting period and after ingestion of a standard oral glucose load (75 g).

Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling.

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 25h by means of membrane-free dermal open-flow microperfusion probes (dOFM) and novel wearable multi-channel pumps.

Methods: Nine psoriatic patients received a topical p-38 inhibitor (BCT194, 0.

Interleukin-6 produced in subcutaneous adipose tissue is linked to blood pressure control in septic patients.

Cytokines are inflammatory mediators of major relevance during sepsis. Recent evidence shows that adipose tissue can produce many distinct cytokines under physiological and pathological conditions, but the role of cytokines produced in adipose tissue was not addressed in sepsis. In the present study the open-flow microperfusion (OFM) technique was used to investigate whether the cytokines produced in subcutaneous adipose tissue (SAT) of patients with severe sepsis correlate with clinical variables.

An automated discontinuous venous blood sampling system for ex vivo glucose determination in humans.

Background: Intensive insulin therapy reduces mortality and morbidity in critically ill patients but places great demands on medical staff who must take frequent blood samples for the determination of glucose levels. A cost-effective solution to this resourcing problem could be provided by an effective and reliable automated blood sampling (ABS) system suitable for ex vivo glucose determination.

Method: The primary study aim was to compare the performance of a prototype ABS system with a manual reference system over a 30 h sampling period under controlled conditions in humans.

Clinical evaluation of subcutaneous lactate measurement in patients after major cardiac surgery.

Minimally invasive techniques to access subcutaneous adipose tissue for glucose monitoring are successfully applied in type1 diabetic and critically ill patients. During critical illness, the addition of a lactate sensor might enhance prognosis and early intervention. Our objective was to evaluate SAT as a site for lactate measurement in critically ill patients.

Subcutaneous adipose tissue exerts proinflammatory cytokines after minimal trauma in humans.

Inflammatory cytokines released from adipose tissue play an important role in different pathological processes. In the present study, we investigated the inflammatory cytokine response of human subcutaneous adipose tissue (SAT) by applying the open-flow microperfusion technique. Four standard 18-gauge microperfusion catheters were inserted into periumbilical SAT of eight healthy male volunteers [29 +/- 3 yr, BMI 24.

Bedside monitoring of subcutaneous interstitial glucose in healthy individuals using microdialysis and infrared spectrometry.

An IR-spectroscopy-based bedside device, coupled to a subcutaneously implanted microdialysis probe, is developed for quasicontinuous glucose monitoring with intermittent readouts at 10-min intervals, avoiding any sensor recalibration under long-term operation. The simultaneous estimation of the microdialysis recovery rate is possible using an acetate containing perfusate and determining its losses across the dialysis membrane. Measurements are carried out on four subjects, with experiments lasting either 8 or 28 h, respectively.

Rapid online-SPE-MS/MS method for ketoprofen determination in dermal interstitial fluid samples from rats obtained by microdialysis or open-flow microperfusion.

Pharmacokinetic studies of topical ketoprofen formulations using continuous sampling techniques such as microdialysis (MD) or open-flow microperfusion (OFM) require sensitive assays due to small sample volumes. A simple and easy online-SPE-MS/MS method for ketoprofen analysis was developed for both MD and OFM samples obtained from rat dermal tissue. The quantification range is 25-5000 ng/ml with a limit of detection of 3 ng/ml using only 10 microl sample volume.

A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir.

Objective: To investigate the pharmacodynamic profile and duration of action for five subcutaneous doses of insulin detemir (0.1, 0.2, 0.

Measurement of interstitial insulin in human adipose and muscle tissue under moderate hyperinsulinemia by means of direct interstitial access.

Insulin's action to stimulate glucose utilization is determined by the insulin concentration in interstitial fluid (ISF) of insulin-sensitive tissues. The concentration of interstitial insulin has been measured in human subcutaneous adipose tissue and skeletal muscle, however, never in parallel. The aim of this study was to compare interstitial insulin levels between both tissue beds by simultaneous measurements and to verify and quantify low peripheral ISF insulin fractions as found during moderate hyperinsulinemia.

Interstitial glucose kinetics in subjects with type 1 diabetes under physiologic conditions.

We investigated the dynamic relationship between interstitial glucose (IG) in the subcutaneous adipose tissue and plasma glucose (PG) during physiologic conditions in type 1 diabetes mellitus (T1DM). Nine subjects with T1DM (5/4 M/F; age, 33 +/- 13 years; body mass index, 26.6 +/- 4.