A5014305035- Pharmaceutical studies and practices
- Pregnancy and Medication Impact
- Antibiotics Pharmacokinetics and Efficacy
- Pregnancy and preeclampsia studies
- HIV/AIDS drug development and treatment
- Pharmacological Effects and Toxicity Studies
- Pharmacogenetics and Drug Metabolism
- Anesthesia and Sedative Agents
- Reproductive System and Pregnancy
- HIV/AIDS Research and Interventions
- Immune Cell Function and Interaction
- Pneumonia and Respiratory Infections
- Helicobacter pylori-related gastroenterology studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Pediatric Pain Management Techniques
- Bioactive Compounds and Antitumor Agents
- Hepatitis C virus research
- Anesthesia and Neurotoxicity Research
- Complement system in diseases
- Child and Adolescent Health
- Folate and B Vitamins Research
- Renal Transplantation Outcomes and Treatments
- Drug Transport and Resistance Mechanisms
- Epilepsy research and treatment
- Liver Disease Diagnosis and Treatment
Radboud University Nijmegen
2014-2025
Radboud University Medical Center
2017-2025
University Medical Center
2020-2023
Radboud Institute for Molecular Life Sciences
2017-2020
Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents. Within multicenter Pharmacokinetics ANtiretroviral agents HIV-infected pregNAnt (PANNA) study, HIV using once daily (50 mg, food) underwent 24-hour pharmacokinetic profiling their third trimester postpartum. Dolutegravir exposure was considered adequate if geometric mean unbound,...
Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) is a severe illness predominantly affecting young children, with limited treatment options beyond supportive care. Eliglustat, approved for Gaucher disease, shows potential in reducing toxin binding to target glomerular endothelial cells vitro, prompting interest as STEC-HUS. However, it remains unknown what dose likely be effective and safe of STEC-HUS the pediatric population. We hypothesize that levels eliglustat...
Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered pregnancy. We combined a physiologically-based pharmacokinetic (PBPK) modeling approach with data on placental transfer to simulate maternal and fetal exposure dolutegravir (DTG). First, PBPK model for DTG in healthy volunteers was established based physiological PK data. Next, extended fetoplacental unit using transplacental...
Dexmedetomidine is currently off-label for use in pediatric clinical care worldwide. Nevertheless, it frequently prescribed to patients as premedication prior induction of anesthesia or procedural sedation. There ample literature on the pharmacokinetics, efficacy and safety dexmedetomidine this vulnerable patient population, but there a general lack consensus dosing. In project, we aimed standardized workflow Dutch Pediatric Formulary establish best evidence-based dosing guidelines The...
Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal fetal doravirine exposure by integrating placenta perfusion experiments pregnancy physiologically based pharmacokinetic (PBPK) modeling.Ex vivo perfusions were performed in a closed-closed configuration, both maternal-to-fetal fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer...
More than half of all drugs are still prescribed off-label to children. Pharmacokinetic (PK) data needed support dosing, however for many such either sparse or not representative. Physiologically-based pharmacokinetic (PBPK) models increasingly used study PK and guide dosing decisions. Building compound requires expertise is time-consuming. Therefore, in this paper, we studied the feasibility predicting pediatric exposure by pragmatically combining existing models, developed e.g. studies...
It is well-accepted that off-label drug dosing recommendations for pediatric patients should be based on the best available evidence. However, traditional evidence often low. To bridge this gap, physiologically-based pharmacokinetic (PBPK) modeling a scientifically well-founded tool can used to enable model-informed (MID) in children clinical practice. In tutorial, we provide pragmatic, PBPK-based workflow. For approach successfully implemented practice, thorough understanding of model...
Physiologically based pharmacokinetic (PBPK) modeling can be an attractive tool to increase the evidence base of pediatric drug dosing recommendations by making optimal use existing (PK) data. A pragmatic approach combining available compound models with a virtual physiology model rational solution predict PK and hence support guidelines for children in real-life clinical care, when it also employed individuals little experience PBPK modeling. This comes within reach as user-friendly...
The placenta acts as a barrier, excluding noxious substances while actively transferring nutrients to the fetus, mediated by various transporters. This study quantified expression of key placental transporters in term human (n = 5) and BeWo, BeWo b30, JEG-3 cell lines. Combining these results with pregnancy physiologically based pharmacokinetic (PBPK) modeling, we demonstrate utility proteomic analysis for predicting drug disposition fetal exposure. Using targeted proteomics quantification...
Currently, tacrolimus is the most potent immunosuppressive agent for renal transplant recipients and commonly prescribed during pregnancy. As data on placental exposure transfer are limited, we studied handling in samples obtained from recipients. We found to venous umbilical cord blood, but particularly noted a strong accumulation. In patient samples, tissue concentrations range of 55-82 ng/g were found. More detailed ex vivo dual-side perfusions term placentas healthy women revealed...
Introduction Critically ill patients show large variability in drug disposition due to e.g., age, size, disease and treatment modalities. Physiologically-based pharmacokinetic (PBPK) models can be used design individualized dosing regimens taking this into account. Dexamethasone, prescribed for the prevention post-extubation stridor (PES), is metabolized by metabolizing enzyme CYP3A. As CYP3A4 undergoes major changes during childhood, we aimed develop age-appropriate recommendations children...
Introduction Modeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal infant gentamicin guidelines, supported by pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach decision implementation. Methods An already existing PBPK model was verified with data of 87 adults, 485 children 912 neonates, based on visual predictive checks predicted-to-observed (PK)...
Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection these drugs this population. Existing compound Simcyp® (v21) were verified adult populations without CKD non-CKD paediatric populations. We developed population reflecting subjects a reduced glomerular filtration tubular secretion, on...
Background Carbamazepine (CBZ) and valproic acid (VPA) are long-standing treatments for epilepsy in children. Interestingly, they display unique drug disposition characteristics maturation of metabolizing enzymes further complicates personalized dosing. Physiologically-based pharmacokinetic (PBPK) modeling includes these mechanisms is hence a promising tool to optimize Our aim better support pediatric dosing CBZ VPA. Methods All VPA simulations were conducted with Simcyp, using available...
<ns3:p>Physiologically based pharmacokinetic (PBPK) models represent computational technology to characterize drug behavior within the context of detailed human physiology. Today, PBPK is routinely used in development and regulatory approval support decisions on how a medicine can be under certain clinical conditions. As such, has potential enhance use for populations that are often under-served globally care, namely pediatric patients, pregnant lactating women. To facilitate broader...
Introduction Doravirine is currently not recommended for pregnant women living with HIV due to the lack of efficacy and safety data. Physiological changes during pregnancy can significantly decrease drug exposure, and, thereby, lower efficacy. Awaiting clinical data, this study aimed predict maternal fetal doravirine exposure by integrating human placenta perfusion experiments physiologically-based pharmacokinetic (PBPK) modelling. Methods An existing validated three-compartment PBPK model a...
Introduction With approximately 50% of the drugs being prescribed off-label, pediatric population is in need for an innovative approach to establish harmonized, best evidence-based dosing guidelines. Physiologically-based pharmacokinetic (PBPK) modelling a valuable predict drug pharmacokinetics (PK) and support dosing. As first step implement PBPK-informed clinical care, we aimed identify suitable verify PBPK prioritize model-informed Methods To select drug, it required be listed on: 1....
Introduction More than half of all drugs are still prescribed off-label to children. To support dosing, pharmacokinetic (PK) data needed. Physiologically-based (PBPK) models increasingly used study PK and guide dosing decisions. We hypothesize that combining existing compound with a paediatric population model can be pragmatically predict exposure. Methods Seven drugs, various characteristics, were selected (i.e. meropenem, ceftazidime, azithromycin, propofol, midazolam, lorazepam,...