Karel Allegaert

Karel Allegaert
University of Leuven, Belgium and Erasmus MC, Rotterdam, the Netherlands · Dpt development and regeneration Dpt of pharmaceutical and pharmacological sciences (KU Leuven) and department of Hospital Pharmacy (Erasmus MC Rotterdam)

MD, PhD

About

833
Publications
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Introduction
neonatologist and clinical pharmacologist, involved in clinical research on PK and PD of drugs in neonates and pregnant women. Also involved in projects to improve neonatal drug development, including the International Neonatal Consortium, the c4c IMI project, the CONCEPTION IMI project, the neonatal HESI effort and the Co-Opt initiative (prenatal steroids, University of Edinburgh

Publications

Publications (833)
Article
Full-text available
Aims: Evidence for drug–drug interactions (DDIs) that may cause age-dependent differences in the incidence and severity of adverse drug reactions (ADRs) in newborns is sparse. We aimed to develop machine learning (ML) algorithms that predict DDI presence by integrating each DDI, which is objectively evaluated with the scales in a risk matrix (proba...
Article
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Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the event of short-term (5 days) nirmatrelvir/ritonavir co-exposure. Therefore, in this report, we identified drugs that require dose adjustment because of drug-drug interactions (DDIs) be...
Article
Integrated in a systems pharmacology approach, pharmacogenetics holds the promise for personalized medicine in neonates. This has been illustrated for some diseases specific to neonates.
Preprint
Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance a...
Article
Neonatal abstinence syndrome (NAS), or—when specifically focused on opioids—neonatal opioid withdrawal syndrome (NOWS) is a withdrawal syndrome in neonates after birth causally related to the in utero exposure to drugs of dependence, and the subsequent acute interruption at delivery [...]
Article
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Red blood cell (RBC) hitchhiking has great potential in enhancing drug therapy, by improving targeting and reducing rapid clearance of nanoparticles (NPs). However, to improve the potential for clinical translation of RBC hitchhiking, a more thorough understanding of the RBC-NP interface is needed. Here, we evaluate the effects of NP surface parame...
Article
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We aimed to evaluate the predictive performance and predicted doses of a single-model approach or several multi-model approaches compared with the standard therapeutic drug monitoring (TDM)-based vancomycin dosing. We performed a hospital-wide monocentric retrospective study in adult patients treated with either intermittent or continuous vancomyci...
Article
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A Teratology Information Service (TIS) does not exist in Belgium yet but will hopefully be established soon. To prepare for this, we aimed to provide insight into the information needs and counseling preferences of the Belgian public and healthcare professionals (HCPs) regarding medication use in pregnancy and breastfeeding. A cross-sectional study...
Article
Introduction: There is a need for structured approaches to inform on pharmacotherapy in preterm neonates. With their proven track record up to regulatory acceptance, physiologically based pharmacokinetic (PBPK) modeling and simulation provide such a structured approach, and hold the promise to support drug development in preterm neonates. Areas c...
Article
Objective: To determine the prevalence of pulmonary hypertension(PAH) in left-sided congenital diaphragmatic hernia(CDH); how we could predict it; and how PAH contributed to the model for mortality prediction. Study design: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day(d)1,7, and a...
Article
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Introduction: There is large variability in kidney function and injury in neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). Acute kidney injury (AKI) definitions that apply categorical approaches may lose valuable information about kidney function in individual patients. Centile serum creatinine (SCr) over postn...
Article
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In neonates, pharmacogenetics has an additional layer of complexity. This is because in addition to genetic variability in genes that code for proteins relevant to clinical pharmacology, there are rapidly maturational changes in these proteins. Consequently, pharmacotherapy in neonates has unique challenges. To provide a contemporary overview on ph...
Poster
INTRODUCTION We aimed to identify signals on the impact of pharmacogenetics (PG) on pharmacokinetics (PK) and –dynamics (PD) in newborns and infants (<1 year). METHODS A structured search was performed (Medline, Embase, WoS]. Applying PRISMA guidelines, studies were selected based on predefined inclusion criteria (infants, PG data, any trial). In a...
Poster
In 2021, a prototype of a Belgian registration system (“BELpREG”) was established, enabling comprehensive data collection on maternal medication use and mother-infant outcomes through online questionnaires. After ‘in-house’ testing on functionality and performance, the feasibility and validity of data collection by the BELpREG prototype will be ass...
Article
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Introduction: Quantitative information on disposition of maternal medicines in human milk remains a major knowledge gap. This case report presents the clinical and pharmacokinetic data of a single mother-infant pair exposed to bosentan and sildenafil for the treatment of pulmonary arterial hypertension (PAH) during lactation. Case presentation: A 4...
Article
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Background Intravenous paracetamol added to morphine reduces postoperative morphine consumption in (near)term neonates. However, there are only sparse data on intravenous paracetamol as multimodal strategy in extremely low birth weight (ELBW) neonates.Objectives This study aims to assess the effects of rescue intravenous paracetamol on postoperativ...
Article
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The hospital can be a stressful environment for a child. To address the increase in demands for pediatric procedural sedation, the PROSA team initiative was started in the Leuven University Hospitals in 2014. In this study, we assessed the efficacy and safety of this project since its initiation. Demographic (age, sex) and clinical (procedure, seda...
Article
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Given the increase in bacterial resistance and the decrease in the development of new antibiotics, the appropriate use of old antimicrobials has become even more compulsory. Clindamycin is a lincosamide antibiotic approved for adults and children as a drug of choice for systemic treatment of staphylococcal, streptococcal, and gram-positive anaerobi...
Article
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Acute kidney injury (AKI) occurs frequently after cardiac surgery in children. Although current diagnostic criteria rely on serum creatinine and urine output, changes occur only after considerable loss of kidney function. This meta-analysis aimed to synthesize the knowledge on novel biomarkers and compare their ability to predict AKI. PubMed/MEDLIN...
Article
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This statement follows the mission of the World Association of Perinatal Medicine in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world with the goal of improving the use of antenatal corticosteroids (ACS) for fetal maturation in Coronavirus Disease 2019 (COVID-19). Pregnant women wit...
Article
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This practice guideline follows the mission of the World Association of Perinatal Medicine (WAPM) in collaboration with the Perinatal Medicine Foundation (PMF), bringing together groups and individuals throughout the world with the goal of improving the use of antenatal corticosteroids (ACS) for fetal maturation. In fact, this document provides fur...
Article
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Background and objective: Clavulanic acid is a commonly used β-lactam inhibitor in pediatrics for a variety of infections. Clear insight into its mode of action is lacking, however, and a target has not been identified. The dosing of clavulanic acid is currently based on that of the partner drug (amoxicillin or ticarcillin). Still, proper dosing o...
Article
Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of preterm and term neonates and infants is important to predict the clearance of renally cleared drugs. This study aims to describe the GFR maturation in (pre)term neonates and young infants (PNA < 90 days) using individual inulin clearance data (CL inulin )...
Article
Full-text available
This practice guideline follows the mission of the World Association of Perinatal Medicine in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world, with the goal of improving the use of antenatal corticosteroids (ACS) for fetal maturation. In fact, this document provides further guidanc...
Article
To truly attain effective and safe pharmacotherapy, the similarities and dissimilarities in physiology between micro-preemies and extreme preterm infants should be explored. The higher incidence of pulmonary hypertension and presence of adrenal insufficiency of prematurity in micro-preemies hereby serve as illustrations. The current limited data on...
Article
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Objective To characterize esophageal motility and esophago-gastric junction (EGJ) function during feeding in neonatal intensive care unit (NICU) patients. Patients and Methods High resolution manometry with impedance (HRIM) was used to investigate esophageal motility and EGJ function in patients admitted to the NICU. Twenty-eight preterm born infa...
Article
Introduction: Paracetamol pharmacokinetics (PK) is highly variable in older fit adults after intravenous administration. Frailty and oral administration likely result in additional variability. The aim was to determine oral paracetamol PK and variability in geriatric inpatients. Methods: A population PK analysis, using NONMEM 7.2, was performed...
Article
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Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker for pharmacovigilance during medication development, a structured search and review on published neonatal QTc values to generate refere...
Article
Full-text available
Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and safety of medical cannabinoids in children. The search included studies through 11-May-2020. Selection criteria included studies evaluating efficacy and safety outcomes of medical c...
Article
Whether preterm birth is associated with cardiac conduction or repolarization abnormalities in later life is still poorly explored, with conflicting data on QTc prolongation in former extreme low birth weight (ELBW, <1000 g) infants. Twelve lead electrocardiograms (ECG) at rest, collected in the PREMATurity as predictor of children’s Cardiovascular...
Article
This research prioritization aimed to identify major research gaps in maternal, newborn, child and adolescent health (MNCAH) to help mitigate the direct and indirect effects of the COVID-19 pandemic. We adapted the Child Health and Nutrition Research Initiative methodology. We defined scope, domains, themes and scoring criteria. We approached diver...
Article
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Background Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants....
Preprint
Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker to assess safety during medication development, a structured search and review on published neonatal QTc values to generate reference va...
Article
Full-text available
Neonatal vitamin K prophylaxis is essential to prevent vitamin K deficiency bleeding (VKDB) with a clear benefit compared to placebo. Various routes (intramuscular (IM), oral, intravenous (IV)) and dosing regimens were explored. A literature review was conducted to compare vitamin K regimens on VKDB incidence. Simultaneously, information on practic...
Article
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Background and Objective Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individuali...
Article
Full-text available
There is a need to assess the knowledge of healthcare providers on the use of maternal analgesics during lactation; however, valid instruments are not yet available. This study aimed to develop and test a valid questionnaire on the knowledge of analgesics (acetaminophen, ibuprofen, aspirin, tramadol, codeine, oxycodone) during lactation, using a st...
Article
Background Vancomycin is a frequently used antibiotic in neonates. However, there is no consensus guideline on the optimal dosing regimen and therapeutic drug monitoring (TDM) practices in this patient population. Objective To document the variability in the current dosing and TDM practices in neonatal intensive care units (NICU). Setting Belgian a...
Preprint
There is a need to assess the knowledge of healthcare providers on the use of maternal analgesics during lactation, while a valid instrument is not yet available. This study aimed to develop a valid and reliable questionnaire on the knowledge of analgesics (acetaminophen, ibuprofen, aspirin, tramadol, codeine, oxycodone) during lactation, using a p...
Article
Background: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. Objective: The aim...
Article
Full-text available
Children show important developmental and maturational changes, which may contribute greatly to pharmacokinetic (PK) variability observed in pediatric patients. These PK alterations are further enhanced by disease-related, non-maturational factors. Specific to the intensive care setting, such factors include critical illness, inflammatory status, a...
Article
Background Intra-partum cefazolin is used to prevent group B Streptococcus (GBS) vertical transmission in mothers allergic to penicillin without a history of anaphylaxis. Objectives To investigate the maternal cefazolin dose–exposure relationship and subsequent maternal and neonatal target attainment at delivery. Methods Data were obtained from 2...
Article
Full-text available
Background: Maternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus....
Article
Full-text available
Background: Cardiac surgery-associated acute kidney injury (CS-AKI) is associated with increased morbidity and mortality in both adults and children. This study aimed to investigate the in-hospital outcomes of CS-AKI in the pediatric population. Methods: PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for stud...
Article
Full-text available
Background: Currently, many initiatives are devoted to optimizing informed consent for participation in clinical research. Due to the digital transformation in health care, a shift toward electronic informed consent (eIC) has been fostered. However, empirical evidence on how to implement eIC in clinical research involving neonates is lacking. Metho...
Article
Full-text available
Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven com...
Article
Current data on use of antihistamines during breastfeeding and risks to the breastfed infant are insufficient. The aim of this systematic review was to provide an overview of studies measuring the levels of antihistamines in human breast milk, estimating the exposure for breastfed infants, and/or reporting possible adverse effects on the breastfed...
Article
Full-text available
Management of neonatal sepsis and the use of antimicrobials have an important impact on morbidity and mortality. However, there is no recent background on which antibiotic regimens are used in different European neonatal intensive care units (NICUs). Our study aimed to describe the use of antibiotics and other aspects of early- and late-onset sepsi...
Article
Full-text available
This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of distribution (3.5–60...
Article
In preterm neonates, physiologically based pharmacokinetic (PBPK) models are suited for studying the effects of maturational and non-maturational factors on the pharmacokinetics of drugs with complex age-dependent metabolic pathways like acetaminophen (APAP). The aim of this study was to determine the impact of drug metabolising enzymes ontogeny on...
Article
Aim: It is currently unclear how paracetamol (acetaminophen) should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of two oral paracetamol formulations and its metabolites in hospitalized octogenarians. Methods: Geriatric inpatients aged 80 years and older...
Article
Full-text available
Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and...
Article
Serum creatinine (sCr) is a commonly measured biomarker to estimate glomerular filtration rate (GFR) and therefore widely used as a covariate in population pharmacokinetic models of renally excreted drugs. In neonates, sCr dynamically changes during the first few weeks after birth. Missing covariates are a common problem in pharmacokinetic modeling...
Presentation
Recent studies have demonstrated that perinatal medication use is also common in Belgium. As in other countries, this entails safety questions and information needs, among patients as well as healthcare professionals (HCP). The research potential of real-world data regarding medication safety is currently underused in Belgium due to a lack of compr...
Article
Background: Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects. Methods: Twelve fetal lambs (127-133 days GA, term 145) were chronically catheterized in utero. Ewes recei...
Article
Background Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking. Methods In this open-label trial conducted at cen...
Article
Full-text available
Many neonates undergoing whole body hypothermia (WBH) following moderate to severe perinatal asphyxia may also suffer from renal impairment. While recent data suggest WBH-related reno-protection, differences in serum creatinine (Scr) patterns to reference patterns were not yet reported. We therefore aimed to document Scr trends and patterns in asph...
Article
Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and...
Chapter
Analgesic dosing regimens should take into account the severity and type of pain, the therapeutic window of the drug, and also the age or developmental state of the child. Translation of these concepts to safe and effective pharmacological management of pain in neonates, infants, and children necessitates a thorough understanding of the principles...
Article
Full-text available
The efficacy and safety of a drug is dose or exposure related, and both are used to assess the benefit‐risk balance of a given drug and ultimately to decide on the specific drug license, including its dose and indication(s). Unfortunately, both efficacy and safety are much more difficult to establish in neonates, resulting in very few drugs license...
Article
In premature infants, effective and safe drug therapy depends on optimal dose selection and requires a thorough understanding of the underlying disease(s) of these fragile infants as well as the pharmacokinetics and pharmacodynamics of the drugs selected to treat their diseases. Differences in gestational and postnatal age or weight are the major d...
Article
Full-text available
Background Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data.Objective The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learnin...
Presentation
Background: Recent studies have shown that perinatal medication use is also common in Belgium. Similar to other countries, this brings safety questions and information needs among patients and healthcare professionals (HCP). The research potential of real-world data regarding medication safety is currently underused in Belgium due to a lack of comp...
Article
Full-text available
Background: nasal or oral sprays are often marketed as medical devices (MDs) in the European Union to prevent common cold (CC), with ColdZyme®/Viruprotect® (trypsin/glycerol) mouth spray claiming to prevent colds and the COVID-19 virus from infecting host cells and to shorten/reduce CC symptoms as an example. We analyzed the published (pre)-clinic...