Stefan Korsatko

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, 0.5% 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 TNFα 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, TNFα release following probe insertion was significantly reduced compared to day 1. CONCLUSIONS Novel membrane-free probes and wearable multi-channel pumps allowed prolonged intradermal 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.

Development and validation of a low cost blood filtration element separating plasma from undiluted whole blood.

Clinical point of care testing often needs plasma instead of whole blood. As centrifugation is labor intensive and not always accessible, filtration is a more appropriate separation technique. The complexity of whole blood is such that there is still no commercially available filtration system capable of separating small sample volumes (10-100 μl) at the point of care. The microfluidics research in blood filtration is very active but to date nobody has validated a low cost device that simultaneously filtrates small samples of whole blood and reproducibly recovers clinically relevant biomarkers, and all this in a limited amount of time with undiluted raw samples. In this paper, we show first that plasma filtration from undiluted whole blood is feasible and reproducible in a low-cost microfluidic device. This novel microfluidic blood filtration element (BFE) extracts 12 μl of plasma from 100 μl of whole blood in less than 10 min. Then, we demonstrate that our device is valid for clinical studies by measuring the adsorption of interleukins through our system. This adsorption is reproducible for interleukins IL6, IL8, and IL10 but not for TNFα. Hence, our BFE is valid for clinical diagnostics with simple calibration prior to performing any measurement.

Use of the Site of Subcutaneous Insulin Administration for the Measurement of Glucose in Patients with Type 1 Diabetes

OBJECTIVE To simplify and improve the treatment of patients with type 1 diabetes, we ascertained whether the site of subcutaneous insulin infusion can be used for the measurement of glucose. RESEARCH DESIGN AND METHODS Three special indwelling catheters (24-gauge microperfusion [MP] catheters) were inserted into the subcutaneous adipose tissue of subjects with type 1 diabetes (n = 10; all C-peptide negative). One MP catheter was perfused with short-acting insulin (100 units/ml, Aspart) and used for insulin delivery and simultaneous glucose sampling during an overnight fast and after ingestion of a standard glucose load (75 g). As controls, the further two MP catheters were perfused with an insulin-free solution (5% mannitol) and used for glucose sampling only. Plasma glucose was measured frequently at the bedside. RESULTS Insulin delivery with the MP catheter was adequate to achieve and maintain normoglycemia during fasting and after glucose ingestion. Tissue glucose concentrations derived with the insulin-perfused catheter agreed well with plasma glucose levels. Median correlation coefficient and median absolute relative difference values were found to be 0.93 (interquartile range 0.91–0.97) and 10.9%, respectively. Error grid analysis indicated that the percentage number of tissue values falling in the clinically acceptable range is 99.6%. Comparable analysis results were obtained for the two mannitol-perfused catheters. CONCLUSIONS Our data suggest that estimation of plasma glucose concentrations from the glucose levels directly observed at the site of subcutaneous insulin infusion is feasible and its quality is comparable to that of estimating plasma glucose concentrations from glucose levels measured in insulin-unexposed subcutaneous tissue.

Counter‐regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: a randomized, placebo‐controlled, double‐blind, crossover trial

To investigate the effect of glucagon‐like peptide 1 receptor agonist liraglutide on the counter‐regulatory hormone response to hypoglycaemia in type 1 diabetes.

Pharmacodynamics of the long‐acting insulin analogues detemir and glargine following single‐doses and under steady‐state conditions in patients with type 1 diabetes

The pharmacodynamic characteristics of the basal insulin analogues insulin detemir (IDet) and insulin glargine (IGlar) have been examined extensively via euglycaemic clamp studies. However, differences in clamp methodology and in the analysis of clamp data between trials have led to confusion over the duration of action of these two insulins. The aim of this study was to address these ambiguities in the literature by assessing the pharmacodynamic properties of IDet and IGlar over 30 h under single‐dose and steady‐state conditions using the definitions and procedures previously standardized by Heise and Pieber in 2007.

Glucose Levels at the Site of Subcutaneous Insulin Administration and Their Relationship to Plasma Levels

OBJECTIVE To examine insulins effect on the tissue glucose concentration at the site of subcutaneous insulin administration. RESEARCH DESIGN AND METHODS A CMA-60 microdialysis (MD) catheter and a 24-gauge microperfusion (MP) catheter were inserted into the subcutaneous adipose tissue of fasting, healthy subjects (n = 5). Both catheters were perfused with regular human insulin (100 units/ml) over a 6-h period and used for glucose sampling and simultaneous administration of insulin at sequential rates of 0.33, 0.66, and 1.00 units/h (each rate was used for 2 h). Before and after the insulin delivery period, both catheters were perfused with an insulin-free solution (5% mannitol) for 2 h and used for glucose sampling only. Blood plasma glucose was clamped at euglycemic levels during insulin delivery. RESULTS Start of insulin delivery with MD and MP catheters resulted in a decline of the tissue glucose concentration and the tissue-to-plasma glucose ratio (TPR) for ∼60 min (P < 0.05). However, during the rest of the 6-h period of variable insulin delivery, tissue glucose concentration paralleled the plasma glucose concentration, and the TPR for MD and MP catheters remained unchanged at 83.2 ± 3.1 and 77.1 ± 4.8%, respectively. After subsequent switch to insulin-free perfusate, tissue glucose concentration and TPR increased slowly and reattained preinsulin delivery levels by the end of the experiments. CONCLUSIONS The results show the attainment of a stable TPR value at the site of insulin administration, thus indicating that insulin delivery and glucose sensing may be performed simultaneously at the same adipose tissue site.

Hospital Glucose Control: Safe and Reliable Glycemic Control Using Enhanced Model Predictive Control Algorithm in Medical Intensive Care Unit Patients

BACKGROUND The aim of this study was to investigate the performance of the enhanced Model Predictive Control (eMPC) algorithm for glycemic control in medical critically ill patients for the whole length of intensive care unit (ICU) stay. METHODS The trial was designed as a single-center, open, noncontrolled clinical investigation in a nine-bed medical ICU in a tertiary teaching hospital. In 20 patients, blood glucose (BG) was controlled with a laptop-based bedside version of the eMPC. Efficacy was assessed by percentage of time within the target range (4.4-6.1 mM; primary end point), mean BG, and BG sampling interval. Safety was assessed by the number of severe hypoglycemic episodes (<2.2 mM). RESULTS Twenty patients (69 +/- 11 years old; body mass index, 27.4 +/- 4.5 kg/m(2); APACHE II, 25.5 +/- 5.2) were included for a period of 7.3 days (median; interquartile range, 4.4-10.2 days) in the study. Time within target range was 58.12 +/- 10.05% (mean +/- SD). For all patients with at least 7 days in the ICU, there was no statistically significant difference between the daily mean percentage of times in target range in respect of the averages. Mean arterial BG was 5.8 +/- 0.5 mM, insulin requirement was 101.3 +/- 50.7 IU/day, and mean carbohydrate intake (enteral and parenteral nutrition) was 176.4 +/- 61.9 g/day. Three hypoglycemic episodes occurred in three subjects, corresponding to a rate of 0.02 per treatment day. CONCLUSIONS In our single-center, noncontrolled study the eMPC algorithm was a safe and reliable method to control BG in critically medical ICU patients for the whole length of ICU stay.

Ultra-Long Pharmacokinetic Properties of Insulin Degludec are Comparable in Elderly Subjects and Younger Adults with Type 1 Diabetes Mellitus

AbstractBackgroundManagement of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia.ObjectiveThe aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults.MethodsThis trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18–35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUCIDeg,τ,SS) (τ = 0–24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (Cmax,IDeg,SS). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUCGIR,τ,SS), and the maximum GIR at steady state (GIRmax,IDeg,SS).ResultsTotal exposure (AUCIDeg,τ,SS) and maximum concentration (Cmax,IDeg,SS) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUCIDeg,τ,SS and Cmax,IDeg,SS and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73–1.47) and 1.02 (95 % CI 0.74–1.39), respectively. Mean AUCIDeg,0–12h,SS/AUCIDeg,τ,SS was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUCGIR,τ,SS (the primary endpoint of this study) and GIRmax,IDeg,SS. Estimated mean age group ratios (elderly/younger adult) for AUCGIR,τ,SS and GIRmax,IDeg,SS and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47–1.31) and 0.80 (95 % CI 0.54–1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects. ConclusionsThe exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes.Clinical trials.gov number: NCT00964418

Clinical applicability of dOFM devices for dermal sampling

Sampling the dermal interstitial fluid (ISF) allows the pharmacokinetics and pharmacodynamics of dermatological drugs to be studied directly at their site of action.

Hypoglycaemic coma due to falsely high point-of-care glucose measurements in an ICU-patient with peritoneal dialysis: a critical incidence report

Sir: Hypoglycaemia is a frequent complication in the establishment of tight glycaemic control by means of intensified insulin therapy [1]. Patients in intensive care are often not capable to communicate the presence of hypoglycaemia-associated adverse events and, thus, the reliability and accuracy of glucose measurements are especially important in this environment [2]. Therefore, every attempt should be taken to ensure that point-of-care glucose testing is reliable and technically unavoidable limitations of devices in certain patient groups are well communicated between industry and ICU personnel. In this context, we report a critical incidence due to falsely high pointof-care glucose measurements in a 68-year-old man with a history of diabetes and continuous ambulatory peritoneal dialysis, who was hospitalised for sepsis. In the morning of the first day the patient was increasingly disorientated and dyspnoeic on the ward. Results of an arterial blood gas analysis (Cobas B221, Roche Diagnostics, glucose oxidase method) showed a glucose value of 183 mg/dl. Peritoneal dialysate was exchanged but due to further deterioration of his condition he was admitted to the ICU in the afternoon. At the ICU a capillary glucose value of 496 mg/dl was attained at 19:00 using a bedside glucose meter [Accu-Chek Go, Roche Diagnostics using GDH-PQQ (glucose dehydrogenase pyrroloquinolinequinone test method)]. Despite aggressive insulin administration (*70 IU over 8 h) no accordant decline of glucose was observed (Fig. 1a). At 2:30 in the morning, the patient developed tachyarrhythmia, but this seemed not to disturb his sleep. The nurse in charge suspected hypokalemia following high-dose insulin infusion to be causal for the formation of arrhythmias, she performed an analysis for electrolytes (Cobas B221, Roche Diagnostics). In fact hypokalemia was present (3.2 mmol/l), but more surprisingly a routinely included blood glucose measurement revealed a value of 38 mg/dl, which was in major disagreement to the capillary measurement performed just before (393 mg/dl). At that time the patient was not asleep, but in a hypoglycaemic coma and regained consciousness promptly after glucose administration. On the next day blood samples of the patient were analysed for glucose with commonly used glucose-meters (Fig. 1b). The falsely high glucose values measured with certain devices