QPS (Netherlands)

Trientine dihydrochloride (TETA-2HCl) is an established treatment for Wilson disease. We assessed different dissolution profiles of TETA-2HCl capsules on the pharmacokinetics (PK) of trientine (TETA) and on direct copper (Cu) parameters. In this open-label, randomized, two way cross-over study, 24 healthy subjects received two single oral doses of 600mg TETA-2HCl with a washout of at least one week; one dose with a fast and one dose with a slow dissolution profile. Blood and urine samples were collected up to 48h for analysis of plasma TETA and its metabolites, N1-acetyltriethylenetetramine (MAT) and N1-N10-diacetyltriethylenetetramine (DAT), serum Cu, ceruloplasmin (Cp) and urinary Cu excretion (UCE). The effect of dissolution profile on the PK was assessed through the ratio of geometric mean ratios (GMRs) and two-sided 90%-confidence intervals (CI) of the fast vs. slow dissolution profile. The Cmax of TETA was comparable for the two products (GMR 95.81%; CI 83.87-109.46%) while AUC0 - inf was slightly lower for the capsules with fast dissolution profile (GMR 90.65; 90% CI 78.32-104.91%). PK parameters were similar for the metabolites of TETA. Additionally, serum Cu and Cp concentrations remained stable over the 12h period after dosing and were comparable between the two products, as was UCE. The pharmacokinetic profiles of TETA after administration of TETA-2HCl capsules with fast and slow dissolution characteristics were similar. Though the lower 90%-CI for AUC0-inf was outside the formal bioequivalence ranges, differences were small (9%) and not considered clinically relevant. A difference in dissolution profile did not affect copper parameters and tolerability.

The OGA inhibitor ASN90/FNP-223 has the potential for disease modification in neurodegenerative diseases. A phase 1 clinical program in healthy participants was performed to determine its suitability for subsequent studies in movement disorders and Alzheimer's disease (AD) patients. Clinical Study 1: A randomized, double-blind, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of single and multiple doses of orally administered ASN90 in healthy adult and elderly participants. Clinical Study 2: A phase 1, open-label, positron emission tomography (PET) study in healthy participants to determine the relationship between plasma concentration and brain target occupancy of ASN90 following a single oral dose. To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and central nervous system (CNS) target engagement of ASN90 in healthy participants. ASN90 was considered safe and well tolerated with dose-proportional pharmacokinetics at steady-state up to oral doses of 500 mg twice daily. Cerebrospinal fluid-to-plasma ratios for mean peak and mean systemic exposures were in the range of 2.5%-4.6%. Investigation of CNS occupancy using a PET ligand demonstrated that target occupancy of greater than 98% in the brain of healthy participants can be achieved at doses that are clinically well tolerated. The phase 1 results of ASN90 in healthy participants provide strong support for its further development in progressive supranuclear palsy (PSP) and AD. Currently, Ferrer Internacional, S.A. is conducting a phase 2 study, known as PROSPER (ClinicalTrials.gov ID: NCT06355531), to evaluate the efficacy, safety, and pharmacokinetics of ASN90 in slowing the progression of PSP. © 2025 International Parkinson and Movement Disorder Society.

Allergen bronchoprovocation test (ABT) has been used to study asthma pathophysiology and as a disease-modelling tool to assess the properties and efficacy of new asthma drugs. In view of the complexity and heterogeneity of asthma, which has driven the definition of several phenotypes and endotypes, we aim to discuss the role of ABT in the era of precision medicine and provide guidance for clinicians how to interpret and use available data to understand the implications for the benefits of asthma treatment. In this review, we summarize background knowledge and applications of ABT and provide an update with recent publications on this topic. In the past years, several studies have been published on ABT in combination with non-invasive and invasive airway samplings and innovative detection techniques allowing to study several inflammatory mechanisms linked to Th2-pathway and allergen-induced pathophysiology throughout the airways. ABT is a valuable research tool, which has strongly contributed to precision medicine by helping to define allergen-triggered key inflammatory pathways and airway pathophysiology, and thus helped to shape our understanding of allergen-driven asthma phenotypes and endotypes. In addition, ABT has been instrumental to assess the interactions and effects of new-targeted asthma treatments along these pathways.

Abstract A7081, 1 S.

Biomarkers for neurodegenerative dementias offer interesting prospects regarding diagnosis and disease monitoring. Monoamines such as dopamine, (nor)adrenaline, serotonin (5-hydroxytryptamine or 5-HT), and their respective metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA), were shown to be altered in dementia, including Alzheimer's disease (AD). Biomarker research is hampered by potential confounds including the influence of time of day and volume of cerebrospinal fluid (CSF) collected. Therefore, the possibility of a circadian rhythm in CSF and plasma, and the presence of a rostrocaudal concentration gradient (RCG) in CSF for aforementioned monoamines/metabolites, were investigated.Circadian rhythmicity was assessed using reversed-phase ultra-high performance liquid chromatography with electrochemical detection (RP-UHPLC-ECD) to measure monoamine/metabolite concentrations in 271 paired CSF and plasma samples, successively collected over a period of 30 h and derived from eight healthy subjects. Plasma samples were also analyzed for melatonin, serving as positive control analyte, using ELISA. The RCG examination entailed RP-UHPLC-ECD analyses on five consecutive CSF samples derived from 10 patients with AD and 10 non-AD/control subjects.Besides a diurnal rhythm for melatonin, we found a similar rhythmicity for plasma HVA, with acrophases occurring between 02:00 and 06:00 h, in four out of seven subjects. Three and two subjects showed a circadian rhythm for CSF HVA and 5-HIAA, respectively. No rhythmicity was observed in any other compound. We found that only CSF MHPG, HVA and 5-HIAA levels differed across CSF fractions, and that these changes in 5-HIAA levels varied in the AD versus non-AD/control group. Positive correlations between CSF volume and HVA and 5-HIAA levels, indicative of a RCG, were also observed. Such a RCG could not be detected for the other monoamines/metabolites. Our results stress the importance of standardizing sampling procedures of biological fluids with respect to time of day, volume and number of samples.

Following the completion of a detailed experimental protocol into the potential inhomogeneity of capillary liquid microsamples, which was performed at seven European Bioanalysis Forum member companies, the summary and conclusion on the data are reported here. It has been demonstrated that it is possible to generate homogeneous samples using these microsampling techniques; that the resultant microsamples can be accurate and precise and that capillary liquid microsampling data can be consistent with conventional larger volume plasma samples. However, the data contain some variability which is contributed to by the different range of experiences that each investigating site had with these techniques. Therefore, knowledge of the compounds, well-designed experiments and experience with these techniques are essential for the delivery of high quality data.

During the last decades, perioperative care for patients with colorectal cancer has shifted towards more standardized care, so-called "enhanced recovery after surgery." Those programs aim to optimize interventions in perioperative care to decrease the rate of postoperative complications, improve patients' recovery, and shorten hospital stay. The purpose of this literature review is to identify, summarize, and operationalize the clinical content of both key interventions and clinical indicators to develop an evidence-based model pathway for surgical patients with colorectal cancer. A systematic search in 3 databases was conducted to identify key interventions (KIs) and indicators to measure the effect of implementation of care pathways. The KIs from the enhanced recovery after surgery protocol were listed and used as framework to identify and match KIs used in the included studies. The Clinical Pathway Compass was used to categorize the indicators. Fifteen studies were included. The number of KI used in the study protocols ranged from 9 to 20. In total, 33 KIs were identified. Little information was available concerning the implementation of and compliance to the protocol. Length of stay and complication rate are the most common used indicators (used in 15/15 and 14/15 of the studies), followed by 21 other measures. All but one of the included studies reported a reduction in length of stay. There is a considerable variation in both number of KIs and indicators as well as operationalization of key interventions, for surgical patients with colorectal cancer documented in literature. Therefore, we summarized the input from different studies and developed an evidence-based model pathway, which can serve as a basis for a local/regional care pathway team to build their own pathway.

The DIA Clinical Data Management Community created a committee to develop a model standard operating procedure (SOP) for writing a data management plan. The goal of the committee was to develop a plan that could be used by industry and academic institutions. The model was based on contributed examples from committee members and their experiences with current practices and technologies. It is understood that as new clinical trial technology is implemented, the SOP will require modification. The model SOP and associated templates are presented as a starting point, and each company or institution will need to modify them to meet its individual needs. The model DMP SOP produced addresses most data management issues that are present in any phase clinical trial while providing a flexible framework.

Current guidelines recommend tailoring of asthma management according to disease control, which is largely defined by increased symptoms and deterioration in lung function. These features do not reflect the severity nor the type of the asthmatic airway inflammation. Fractional exhaled nitric oxide (FE(NO)) is a simple, non-invasive and cost-effective online test applicable in both adults and children. In addition to symptoms and lung function measurements, FE(NO) reflects airway eosinophilia and hence allows online assessment of the corticosteroid-sensitive T helper 2 type airway inflammation in asthmatic patients. FE(NO) can thus be applied to aid asthma diagnosis and treatment monitoring both in clinical practice and for research purposes. The scope of this review is to provide an overview of the most important clinical studies using FE(NO) in asthma management and to summarise the implications of FE(NO) measurements in clinical practice. In several studies, FE(NO) measurements provided additional information on aspects of asthma including phenotyping, corticosteroid-responsiveness and disease control. Thus, if correctly applied and interpreted, FE(NO) can aid asthma diagnosis, identify patients at risk of exacerbation and support customized treatment decisions. A simple and reliable tool to quantify peripheral nitric oxide will further aid to identify patients with small airways inflammation.