Stability and compatibility of vancomycin for administration by continuous infusion.

BACKGROUND: Vancomycin is increasingly used by continuous infusion, but few specific data are available about stability under practical conditions of preparation and use, and compatibility with other intravenous drugs commonly used in the routine hospital setting. METHODS: Vancomycin stability [defined as recovery ≥ 93% of the original content (validated HPLC assay)] was examined throughout the whole process of centralized preparation, storage and use in the ward by infusion for up to 48 h, with allowances for deviations from recommended practice [exposure to high temperature; use of concentrated solutions (up to 83 g/L)]. Compatibility was assessed by mimicking co-administration in a single line via Y-shaped connectors with contact of 1 h at 25°C, followed by visual inspection (professional viewer), detection of particulate matter (particle analyser) and HPLC assay of vancomycin. RESULTS: Vancomycin was stable during the whole process and also during 72 h exposure of concentrated solutions at temperatures up to 37°C. Major incompatibilities were seen with ß-lactams (temocillin, piperacillin/tazobactam, ceftazidime, imipenem, cefepime and flucloxacillin) and moxifloxacin, but not with ciprofloxacin, aminoglycosides and macrolides. Propofol, valproic acid, phenytoin, theophylline, methylprednisolone and furosemide were also incompatible, whereas ketamine, sufentanil, midazolam, morphine, piritramide, nicardipine, urapidil, dopamine, dobutamine and adrenaline were compatible. No effect or incompatibility with N-acetyl-cysteine or amino acid solutions was detected. CONCLUSIONS: Centralized preparation of vancomycin and its use by continuous infusion in wards is safe concerning stability, but careful attention must be paid to incompatibilities. Several drugs (including all ß-lactams) require distinct intravenous lines or appropriate procedures to avoid undue contact.

First-in-human development of a pharmacodynamic biomarker for PAC1 receptor antagonists using intradermal injections of maxadilan.

Maxadilan, a potent vasodilator peptide, selectively activates the PAC1 receptor, a promising target for migraine therapy. Therefore, maxadilan has been suggested as a tool to study the pharmacodynamics (PDs) of PAC1 receptor antagonists. The objectives of this first-in-human study were to: (1) determine the safety, tolerability, dose response, and time course of the dermal blood flow (DBF) changes after intradermal (i.d.) injections of maxadilan in the human forearm, and (2) assess the inter-arm and inter-period reproducibility of this response. This was a single-center, open-label study in healthy subjects, comprising three parts: (1) dose-response (n = 25), (2) response duration (n = 10), and (3) reproducibility (n = 15). DBF measurements were performed using laser Doppler imaging (LDI) up to 60 min postinjection, or up to 5 days for the response duration assessments. To assess reproducibility, the intraclass correlation coefficient (ICC) and sample sizes were calculated. The i.d. maxadilan (0.001, 0.01, 0.1, 0.9, 3, and 10 ng) produced a well-tolerated, dose-dependent increase in DBF, with a half-maximal effective concentration fitted at 0.0098 ng. The DBF response to 0.9 ng maxadilan was quantifiable with LDI up to 72 h postinjection. The inter-period reproducibility of the DBF response was better upon 0.9 ng (ICC > 0.6) compared to 0.01 ng (ICC < 0.4) maxadilan. However, irrespective of the study design or maxadilan dose, a sample size of 11 subjects is sufficient to detect a 30% difference in DBF response with 80% power. In conclusion, intradermal maxadilan provides a safe, well-tolerated, and reproducible PD biomarker for PAC1 receptor antagonists in vivo in humans.

Co-creation with research participants to inform the design of electronic informed consent.

Objective: This study aimed to provide recommendations for a personalized electronic informed consent interface that is adapted to research participants' needs and could enable a longitudinal interaction between the participants and the research team. Methods: The co-creation process consisted of three co-creation workshops, one focus group discussion, and four semi-structured interviews. In total, 24 participants, who had taken part in four disparate clinical studies in Belgium, were involved. Descriptive statistics and qualitative content analysis were applied to analyze the survey data and audio recordings. Results: Varying perceptions on the type and amount of information described in an informed consent form were reported. Other findings were related to the structure and presentation of information, setting preferences for data sharing, and electronically signing new informed consent versions. Regarding the long-term interaction, most of the participants wanted to receive progress updates, including the results, of the study in which they had taken part. They proposed to receive a notification, preferably via email, in case new information is made available on the electronic informed consent interface. Conclusions: To optimally support the design of an electronic informed consent interface, it is key to understand the research participants' needs. Study findings suggest that an electronic informed consent interface may be a promising technological application to interactively provide study-related information and to keep participants informed during and after the clinical study.

Pharmacokinetics of Oral Rebaudioside A in Patients with Type 2 Diabetes Mellitus and Its Effects on Glucose Homeostasis: A Placebo-Controlled Crossover Trial.

BACKGROUND AND OBJECTIVES: Rebaudioside A, a steviol glycoside, is deglycosylated by intestinal microflora prior to the absorption of steviol and conjugation to steviol glucuronide. While glucose-lowering properties are observed for rebaudioside A in mice, they have been attributed to the metabolites steviol and steviol glucuronide. We aimed to characterize the pharmacokinetic and pharmacodynamic properties of rebaudioside A and its metabolites in patients with early-onset type 2 diabetes mellitus (T2DM). METHODS: This randomized, placebo-controlled, open-label, two-way crossover trial was performed in subjects with T2DM on metformin or no therapy at the University Hospitals Leuven, Belgium. Following oral rebaudioside A (3 g), plasma concentrations of rebaudioside A, steviol and steviol glucuronide were determined. The effect on glucose homeostasis was examined by an oral glucose tolerance test (OGTT) performed 19 h following rebaudioside A administration, i.e. the presumed time of maximal steviol and steviol glucuronide concentrations. The primary pharmacodynamic endpoint was the difference in area under the blood glucose concentration-time curve during the first 2 h of the OGTT (AUCGlucose(0-2h)) for rebaudioside A vs. placebo. RESULTS: In total, 30 subjects [63.5 (57.8-69.0) years of age, 86.7% male] completed the trial. Rebaudioside A was detected as early as 1 h after administration in nearly all subjects. As expected, steviol and steviol glucuronide reached their maximal concentrations at 19.5 h following rebaudioside A administration. Rebaudioside A did not lower the AUCGlucose(0-2h) compared to placebo (- 0.7 (95% CI - 22.3; 20.9) h·mg/dL, P = 0.95). Insulin and C-peptide concentrations were also comparable between both conditions (P > 0.05). CONCLUSION: Rebaudioside A is readily absorbed after oral administration and metabolized to steviol and steviol glucuronide. However, no effect on glucose nor insulin or C-peptide excursion was observed during the OGTT at the time of maximal metabolite concentrations. Thus, no antidiabetic properties of rebaudioside A could be observed in patients with T2DM after single oral use. CLINICAL TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT03510624).

Implementation of a protocol for administration of vancomycin by continuous infusion: pharmacokinetic, pharmacodynamic and toxicological aspects.

Optimising antibiotic administration is critical when dealing with pathogens with reduced susceptibility. Vancomycin activity is dependent on the area under the concentration-time curve over 24 h at steady-state divided by the minimum inhibitory concentration (AUC/MIC), making continuous infusion (CI) or conventional twice daily administration pharmacodynamically equipotent. Because CI facilitates drug administration and serum level monitoring, we have implemented a protocol for CI of vancomycin by: (i) examining whether maintaining stable serum concentrations (set at 25-30 mg/L based on local susceptibility data of Gram-positive target organisms) can be achieved in patients suffering from difficult-to-treat infections; (ii) assessing toxicity (n = 94) and overall efficacy (n = 59); and (iii) examining the correlation between AUC/MIC and the clinical outcome in patients for whom vancomycin was the only active agent against a single causative pathogen (n = 20). Stable serum levels at the expected target were obtained at the population level (loading dose 20mg/kg; infusion of 2.57 g/24 h adjusted for creatinine clearance) for up to 44 days, but large intrapatient variations required frequent dose re-adjustments (increase in 57% and decrease in 16% of the total population). Recursive partitioning analysis of AUC/MIC ratios versus success or failure suggested threshold values of 667 (total serum level) and 451 (free serum level), corresponding to organisms with a MIC>1 mg/L. Nephrotoxicity potentially related to vancomycin was observed in 10% of patients, but treatment had to be discontinued in only two of them.

Correlation between free and total vancomycin serum concentrations in patients treated for Gram-positive infections.

Routine therapeutic drug monitoring (TDM) reports only total vancomycin (VAN) concentrations, although protein binding varies and it is generally accepted that only free VAN is active. The aims of this study were to examine the correlation between free and total VAN concentrations in order to estimate whether free VAN levels can be predicted based on its total concentration. A high-performance liquid chromatography (HPLC) method was set up and validated (against routine laboratory immunoassays) for measurement of free [ultrafiltration (Centrifree); cut-off 30 kDa] and total [solid-phase extraction (Oasis MCX cartridge)] VAN in serum. Samples (n=65) from patients (n=15) treated by continuous infusion were analysed. There was a wide variation in free to total VAN ratios [range 12-100%; mean 63.6+/-25.8%, with 59 values falling outside the 95% confidence interval (57.3-69.9%); median 70.2%]. The correlation between free and total VAN was poor (R(2)=0.55). Artefacts such as pH variation of sera could be excluded. Both intrapatient and interpatient variabilities were large and no correlation could be made with patients' clinical conditions. Total VAN concentration is not predictive of free VAN concentration, suggesting that actual determination of free VAN might be recommended as an improved method of TDM.