A5075422062- Antibiotics Pharmacokinetics and Efficacy
- Antibiotic Resistance in Bacteria
- Sepsis Diagnosis and Treatment
- Pneumonia and Respiratory Infections
- Inhalation and Respiratory Drug Delivery
- Evolution and Genetic Dynamics
- Immune Response and Inflammation
- Statistical Methods in Clinical Trials
- Pharmacogenetics and Drug Metabolism
- Inflammation biomarkers and pathways
- Innovative Microfluidic and Catalytic Techniques Innovation
- S100 Proteins and Annexins
- Protein purification and stability
- Health Systems, Economic Evaluations, Quality of Life
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Peripheral Neuropathies and Disorders
- Immune Cell Function and Interaction
- Pharmaceutical and Antibiotic Environmental Impacts
- Ion channel regulation and function
- Urinary Tract Infections Management
- Blood groups and transfusion
- Myasthenia Gravis and Thymoma
- Optimal Experimental Design Methods
- Microscopic Colitis
Freie Universität Berlin
2022-2025
Centre for Human Drug Research
2018-2024
Leiden University
2018-2024
Inserm
2022
École des Hautes Études en Santé Publique
2022
Université de Rennes
2022
Institut de Recherche en Santé, Environnement et Travail
2022
Leiden University Medical Center
2022
Uppsala University
2015
Collateral sensitivity (CS)-based antibiotic treatments, where increased resistance to one leads a second antibiotic, may have the potential limit emergence of antimicrobial resistance. However, it remains unclear how best design CS-based treatment schedules. To address this problem, we use mathematical modelling study effects pathogen- and drug-specific characteristics for different designs on bacterial population dynamics evolution. We confirm that simultaneous one-day cycling treatments...
Mycobacterium tuberculosis can exist in different states vitro, which be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. could provide a framework for accurate characterization drug effects on bacterial states. The data H37Rv used this study consisted viability defined cfu versus time based from an vitro hypoxia system. External validation model was conducted using representing rate incorporation radiolabelled methionine into...
Significance A promising strategy to overcome the evolution of antibiotic-resistant bacteria is use collateral sensitivity-informed antibiotic treatments that rely on cycling or mixing antibiotics, such resistance toward one confers increased sensitivity other. Here, focusing multistep fluoroquinolone in Streptococcus pneumoniae , we show induces diverse responses whose magnitude and direction are determined by allelic identity. Using mathematical simulations, these effects can be exploited...
Abstract Hepatitis E virus (HEV) is endemic in Europe. However, standardized methods for the surveillance of HEV viremia general population are lacking. This study aimed to compare incidence among blood donors two European countries, Germany and Portugal, during period 2015‐2018. The seasonal distribution infection, as well host risk factors including age, sex, group phenotype were explored. A total 191,236 donations from Portugal tested RNA plasma mini‐pools up 96 using an internally...
Cefazolin is used as a prophylactic antibiotic to reduce surgical site infections (SSIs). Obesity has been identified risk factor for SSIs. dosing recommendations and guidelines are currently inconsistent obese patients. As plasma target-site exposure might differ, pharmacokinetic data from the sites of SSIs essential evaluate treatment efficacy: these can be obtained via tissue microdialysis. This analysis was designed need adaptations in patients prophylaxis. Data 15 (BMImedian = 52.6 kg...
Acute inflammation caused by infections or sepsis can impact pharmacokinetics. We used a model-based analysis to evaluate the effect of acute as represented interleukin-6 (IL-6) levels on drug clearance, focusing renal glomerular filtration rate (GFR) and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. A physiologically based model incorporating hepatic clearance was implemented. Functions correlating IL-6 with GFR in vitro CYP3A4 activity were derived incorporated into modeling framework....
Clinical studies in healthy volunteers challenged with lipopolysaccharide (LPS), a constituent of the cell wall Gram‐negative bacteria, represent key model to characterize Toll‐like receptor 4 (TLR4)‐mediated inflammatory response. Here, we developed mathematical modelling framework quantitatively dynamics and inter‐individual variability multiple biomarkers volunteer LPS challenge studies. Data from previously reported were used, which included individual‐level time‐course data for tumour...
Voriconazole (VRC), a broad-spectrum antifungal drug, exhibits nonlinear pharmacokinetics (PK) due to saturable metabolic processes, autoinhibition and metabolite-mediated inhibition on their own formation. VRC PK is also characterised by high inter- intraindividual variability, primarily associated with cytochrome P450 (CYP) 2C19 genetic polymorphism. Additionally, recent in vitro findings indicate that main metabolites, voriconazole N-oxide (NO) hydroxyvoriconazole (OHVRC), inhibit CYP...
NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances excitability, improving contractility strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated safety, pharmacokinetics, pharmacodynamics single multiple doses healthy male female subjects. Single-ascending (50-1,600 mg)...
Sepsis is a life-threatening condition driven by the dysregulation of host immune response to an infection. The complex and interacting mechanisms underlying sepsis remain not fully understood. By integrating prior knowledge from literature using mathematical modelling techniques, we aimed obtain deeper mechanistic insight into pathogenesis evaluate promising novel therapeutic targets, with focus on Toll-like receptor 4 (TLR4)-mediated pathways. A Boolean network regulatory relationships was...
Asymptomatic blood donors can transmit human parvovirus B19 (B19V).We assessed the B19V prevalence among a large cohort of donations collected in Germany during 2015-2018.In total, 167 123 were screened for deoxyribonucleic acid with 22 cases viremia identified (0.013% positive). Infections peaked at 4-year interval and highest number occurred summer months. All infections found rhesus D-antigen-positive donations, suggesting protective factor who lack this antigen.These findings contribute...
Prediction of antimicrobial target-site pharmacokinetics is relevance to optimize treatment with agents. A physiologically based pharmacokinetic (PBPK) model framework was developed for prediction pulmonary pharmacokinetics, including key infection sites (i.e. the alveolar macrophages and epithelial lining fluid).The modelling incorporated three lung PBPK models: a general passive permeability-limited model, drug-specific quantitative structure-property relationship (QSPR)-informed...
Abstract Collateral sensitivity (CS), which arises when resistance to one antibiotic increases towards other antibiotics, offers novel treatment opportunities constrain or reverse the evolution of antibiotic-resistance. The applicability CS-informed treatments remains uncertain, in part because we lack an understanding generality CS effects for different mutations, singly combination. Here address this issue Gram-positive pathogen Streptococcus pneumoniae by measuring collateral and fitness...
In this study, we describe the kinetics of a new potential inflammatory biomarker, presepsin, together with panel well-established biomarkers in human endotoxemia study. We evaluated biomarker correlations and identified combinations that could hold valuable insights regarding state infection.
In preclinical investigations, for example, in vitro, vivo, and silico studies, the pharmacokinetic, pharmacodynamic, toxicological characteristics of a drug are evaluated before advancing to first-in-man trial. Usually, each study is analyzed independently human dose range does not leverage knowledge gained from all studies. Taking into account data through inferential procedures can be particularly interesting obtaining more precise reliable starting range. Our objective propose Bayesian...
Congenital adrenal hyperplasia (CAH) is characterized by impaired cortisol production. Hydrocortisone (synthetic cortisol) the drug-of-choice for replacement therapy, aiming to mimic physiological circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls production through pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. aim of this study was quantify key mechanisms involved in HPA activity regulation their interaction with hydrocortisone therapy. Data...
Conventionally, a first-in-human phase I trial in healthy volunteers aims to confirm the safety of drug humans. In such situations, should not suffer from any issues and simple algorithm-based dose-escalation schemes are often used. However, avoid too many clinical trials future, it might be appealing design these accumulate information on link between dose efficacy/activity under strict constraints. Furthermore, an increasing number molecules for which dose-activity curve reaches plateau emerging.