A5061422529- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Pharmaceutical studies and practices
- Pharmacological Effects and Toxicity Studies
- Metabolism and Genetic Disorders
- Antibiotics Pharmacokinetics and Efficacy
- Anesthesia and Sedative Agents
- Orthopedic Infections and Treatments
- Chemistry and Chemical Engineering
- Pesticide Exposure and Toxicity
- Poisoning and overdose treatments
- Psychedelics and Drug Studies
- Histone Deacetylase Inhibitors Research
- Health Systems, Economic Evaluations, Quality of Life
- Gastroesophageal reflux and treatments
- Epigenetics and DNA Methylation
- Forensic Toxicology and Drug Analysis
- Liver Disease Diagnosis and Treatment
- Cancer-related gene regulation
- Pharmaceutical Economics and Policy
- Esophageal and GI Pathology
- Clinical practice guidelines implementation
- Amino Acid Enzymes and Metabolism
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
Roche (Switzerland)
2020-2023
Erasmus MC - Sophia Children’s Hospital
2016-2021
Radboud University Nijmegen
2016-2021
University of Florida
2019-2021
Erasmus MC
2016-2021
Radboud University Medical Center
2016-2021
UCB Pharma (Belgium)
2021
University of Antwerp
2021
KU Leuven
2021
Novartis (Switzerland)
2021
Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen cortical tissues (preterm newborns to adults) a subset 62 tissue samples, we measured mRNA levels 11 transcription factor pregnane X receptor (PXR) with quantitative real‐time polymerase chain reaction, protein abundance nine using liquid chromatography tandem mass spectrometry selective reaction...
The human absorption, distribution, metabolism, and excretion (hADME) study is the cornerstone of clinical pharmacology package for small molecule drugs, providing comprehensive information on rates routes disposition elimination drug-related material in humans through use
The intestinal influx oligopeptide transporter peptide 1 (PEPT1) (<i>SLC15A1</i>) is best known for nutrient-derived di- and tripeptide transport. Its role in drug absorption increasingly recognized. To better understand the disposition of PEPT1 substrate drugs young infants, we studied mRNA expression tissue localization across pediatric age range. was determined using real-time reverse-transcription polymerase chain reaction small tissues collected from surgical procedures (neonates...
Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study relation age with absolute transporter protein expression a cohort 62 mainly fetus newborn samples.Protein expressions BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 ATP1A1 were quantified LC-MS/MS isolated crude fractions snap-frozen post-mortem fetal pediatric, surgical adult liver samples. mRNA was using RNA...
Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little known maturation protein expression levels, especially during early life. We aimed to study the 10 liver tissue from fetuses, infants, adults. Transporter levels [ATP-binding cassette (ABC)B1, ABCG2, ABCC2, ABCC3, bile salt efflux pump, glucose 1, monocarboxylate organic anion polypeptide (OATP)1B1,...
Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug‐metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It frequently administered orally to children, yet knowledge lacking on oral bioavailability in term neonates up until 1 year of age. Furthermore, dispositions major metabolites 1‐OH‐midazolam (OHM) 1‐OH‐midazolam‐glucuronide (OHMG) after administration are largely unknown for entire pediatric age span. We aimed fill these gaps with a [ 14 C]midazolam...
Drug disposition in children may vary from adults due to age-related variation drug metabolism. Microdose studies present an innovation study pharmacokinetics (PK) paediatrics; however, they should be used only when the PK is dose linear. We aimed assess linearity of a [14 C]midazolam microdose, by comparing intravenous (IV) microtracer (a microdose given simultaneously with therapeutic midazolam dose), single isolated microdose.Preterm 2-year-old infants admitted intensive care unit...
Background : Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed develop model-informed using published pharmacokinetic data a decision framework adjust dosing guidelines based on these doses, piperacillin amikacin in critically ill children as proof concept. Methods Piperacillin models were extracted from literature. Concentration-time profiles simulated for various regimens...
Omeprazole is a proton pump inhibitor that used in acid suppression therapy infants. Infants cannot swallow the oral tablets or capsules. Since, infants require non-standard dose of omeprazole, granules are often crushed suspended water sodium bicarbonate, which may destroy enteric coating. In this study we explore efficacy and pharmacokinetics rectally administered omeprazole with gastroesophageal reflux disease (GERD) due to esophageal atresia (EA) congenital diaphragmatic hernia (CDH)...
The hepatic influx transporter OATP1B1 (SLCO1B1) plays an important role in the disposition of endogenous substrates and drugs prescribed to children. Alternative splicing increases diversity protein products from > 90% human genes may be triggered by developmental signals. As concentrations several change during growth development, with this exploratory study we investigated age‐dependent alternative SLCO1B1 mRNA 97 postmortem livers (fetus‐adolescents). Twenty‐seven splice variants were...
Abstract Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically‐based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ontogeny profiles activity children, especially neonates, to predict drug disposition. Therefore, expression measurements from human kidney postmortem cortical tissue samples were normalized represent a fraction mature Using these data,...
Background: Gamma-hydroxybutyric acid (GHB) is a recreational drug with central nervous system depressing effects that often abused. A urine GHB point-of-care test can be of great diagnostic value. The objective this prospective study was to determine the performance new DrugCheck Single Test and Viva-E immunoassay for samples in emergency department patients. Methods: Patients presented OLVG hospital Amsterdam Glasgow Coma Scale score <15 potential abuse intoxication were included study....
Growth and development affect drug-metabolizing enzyme activity thus could alter the metabolic profile of a drug. Traditional studies to create metabolite profiles study routes excretion are unethical in children due high radioactive burden. To overcome this challenge, we aimed show feasibility an absorption, distribution, metabolism, (ADME) using [14 C]midazolam microtracer as proof concept children. Twelve stable, critically ill received oral (20 ng/kg; 60 Bq/kg) while receiving...
Hartman, Stan; Swaving, Joost; Beek, Stijn Van; Groen, Bianca De Hoop, Marika; van der Zanden, Tjitske; Heine, Rob Ter; Wildt, Saskia Author Information
Drug disposition in children is impacted by developmental changes drug absorption, distribution, metabolism and excretion. This mandates the need for dosing regimens specifically tailored to children. Yet, there are gaps knowledge on these changes, example regarding hepatic renal transport metabolism, putting at risk subtherapeutic or toxic exposure. Pediatric research faced with ethical analytical challenges. review addresses how can be filled challenges overcome using innovative study designs.
Aims & Objectives: Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed develop model-informed using published pharmacokinetic data a decision framework adjust dosing guidelines based on these doses, piperacillin amikacin in critically ill children as proof concept. Methods: Piperacillin models were extracted from literature. Concentration-time profiles simulated for various...