Striving for balance in decisions on antenatal pharmacotherapy.

Most individuals use medication during pregnancy. However, decision making on antenatal pharmacotherapy presents considerable ethical and scientific challenges. Amid a sociocultural paradigm prioritising the elimination of fetal risks, available evidence and guidance are limited, and current decision making on antenatal drugs mostly proceeds in an ad-hoc and, often, biased manner.

Enteroids to Study Pediatric Intestinal Drug Transport.

Intestinal maturational changes after birth affect the pharmacokinetics (PK) of drugs, having major implications for drug safety and efficacy. However, little is known about ontogeny-related PK patterns in the intestine. To explore the accuracy of human enteroid monolayers for studying drug transport in the pediatric intestine, we compared the drug transporter functionality and expression in enteroid monolayers and tissue from pediatrics and adults.

A User-Driven Framework for Dose Selection in Pregnancy: Proof of Concept for Sertraline.

Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic modeling and expanding clinical data in pregnancy may support antenatal doses. We aimed to develop and pilot a comprehensive and user-driven Framework for Dose Selection in Pregnancy to support the clinical implementation of a best-evidence antenatal dose for sertraline.

Willingness-to-use and preferences for model-informed antenatal doses: a cross-sectional study among European healthcare practitioners and pregnant women.

Physiological changes in pregnancy may affect drug safety and efficacy, sometimes requiring dose adjustments. Pregnancy-adjusted doses, however, are missing for most medications. Increasingly, pharmacokinetic models can be used for antenatal dose finding.

Human enteroid monolayers as a potential alternative for Ussing chamber and Caco-2 monolayers to study passive permeability and drug efflux.

After oral administration, the intestine is the first site of drug absorption, making it a key determinant of the bioavailability of a drug, and hence drug efficacy and safety. Existing non-clinical models of the intestinal barrier in vitro often fail to mimic the barrier and absorption of the human intestine. We explore if human enteroid monolayers are a suitable tool for intestinal absorption studies compared to primary tissue (Ussing chamber) and Caco-2 cells.

Age-Specific ADME Gene Expression in Infant Intestinal Enteroids.

In childhood, developmental changes and environmental interactions highly affect orally dosed drug disposition across the age range. To optimize dosing regimens and ensure safe use of drugs in pediatric patients, understanding this age-dependent biology is necessary. In this proof-of-concept study, we aimed to culture age-specific enteroids from infant tissue which represent its original donor material, specifically for drug transport and metabolism.

The potential of enteroids derived from children and adults to study age-dependent differences in intestinal CYP3A4/5 metabolism.

Drug metabolism in the intestinal wall affects bioavailability of orally administered drugs and is influenced by age. Hence, it is important to fully understand the drug metabolizing capacity of the gut to predict systemic exposure. The aim of this study was to investigate the potential of enteroids as a tool to study CYP3A4/5 -mediated metabolism in both children and adults.

Demystifying physiologically based pharmacokinetic modelling among non-modelers towards model-informed medicine use in under-served populations.

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 drug development and regulatory approval to support decisions on how a medicine can be used under certain clinical conditions. As such, PBPK has the potential to enhance medicine use for populations that are often under-served globally in drug development and clinical care, namely pediatric patients, pregnant and lactating women.

Getting the dose right using physiologically-based pharmacokinetic modeling: dexamethasone to prevent post-extubation stridor in children as proof of concept.

Introduction: Critically ill patients show large variability in drug disposition due to e.g., age, size, disease and treatment modalities.

Perceived barriers and facilitators for model-informed dosing in pregnancy: a qualitative study across healthcare practitioners and pregnant women.

Background: Most women use medication during pregnancy. Pregnancy-induced changes in physiology may require antenatal dose alterations. Yet, evidence-based doses in pregnancy are missing.

Potentially Life-Threatening Interaction between Opioids and Intrathecal Baclofen in Individuals with a Childhood-Onset Neurological Disorder: A Case Series and Review of the Literature.

Background: Spasticity and dystonia are movement impairments that can occur in childhood-onset neurological disorders. Severely affected individuals can be treated with intrathecal baclofen (ITB). Concomitant use of ITB and opioids has been associated with central nervous system (CNS) depression.

Optimization of the betamethasone and dexamethasone dosing regimen during pregnancy: a combined placenta perfusion and pregnancy physiologically based pharmacokinetic modeling approach.

Background: Antenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome (RDS). The current treatment regimens, effective to prevent neonatal RDS, may be suboptimal. Recently, concerns have been raised regarding possible adverse long-term neurological outcomes due to high fetal drug exposures.

Risk of cancer in patients with bile acid diarrhoea: a Danish nationwide matched cohort study.

Objective: Bile acid diarrhoea is a common cause of chronic diarrhoea. Increased levels of potentially carcinogenic bile acids in faeces, theoretically, may increase the risk of colorectal cancer in particular, but the long-term disease course is unknown. We aimed to investigate the overall and site-specific cancer risk in bile acid diarrhoea.

Number of intraepithelial lymphocytes and presence of a subepithelial band in normal colonic mucosa differs according to stainings and evaluation method.

Chronic watery diarrhea is a frequent symptom. In approximately 10% of the patients, a diagnosis of microscopic colitis (MC) is established. The diagnosis relies on specific, but sometimes subtle, histopathological findings.

[Adequate medication doses for pregnant women and their unborn children].

Most women use medication during pregnancy. The disposition of drugs may be altered due to changes in pregnant women's bodies. This may call for pregnancy-adjusted doses for certain medications.

Towards More Robust Evaluation of the Predictive Performance of Physiologically Based Pharmacokinetic Models: Using Confidence Intervals to Support Use of Model-Informed Dosing in Clinical Care.

Background And Objective: With the rise in the use of physiologically based pharmacokinetic (PBPK) modeling over the past decade, the use of PBPK modeling to underpin drug dosing for off-label use in clinical care has become an attractive option. In order to use PBPK models for high-impact decisions, thorough qualification and validation of the model is essential to gain enough confidence in model performance. Currently, there is no agreed method for model acceptance, while clinicians demand a clear measure of model performance before considering implementing PBPK model-informed dosing.

Pain during the first year after scoliosis surgery in adolescents, an exploratory, prospective cohort study.

Objective: Approximately 50% of adolescents who have undergone scoliosis surgery still experience severe pain one year postoperatively. We explored the postoperative pain trajectory and the potential value of preoperative Thermal Quantitative Sensory Testing (T-QST) as predictor of chronic postsurgical pain after scoliosis surgery.

Design: Single-center prospective cohort study in adolescents undergoing scoliosis surgery.

Infant Ustekinumab Clearance, Risk of Infection, and Development After Exposure During Pregnancy.

Background: Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life.

Methods: Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

Background: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH.

Objective: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents.

Development and performance of the c4c national clinical trial networks for optimizing pediatric trial facilitation.

Introduction: The high failure rate of industry-driven pediatric clinical trials leads to insufficient timely labeling of drugs in children and a lack of scientific evidence, resulting in the persistently high off-label drug use. National clinical trial networks can facilitate collaboration between sites, investigators, and experts, increasing the likelihood of successful trials. Within the conect4children (c4c) network, an Innovative Medicines Initiative 2-funded project, National Hubs hosted by National Clinical Trials Networks were set up across 21 European countries to facilitate the setup and execution of pediatric clinical trials.

Influence of Age, Heart Failure and ACE Inhibitor Treatment on Plasma Renin Activity in Children: Insights from a Systematic Review and the European LENA Project.

Background: Plasma renin activity (PRA) has gained relevance as prognostic marker in adults with heart failure. The use of PRA as a clinically meaningful parameter in children and children with heart failure requires a thorough knowledge of the factors that influence PRA to correctly assess PRA levels. We aim to evaluate the influence of age, heart failure and angiotensin-converting enzyme inhibitor (ACEi) on PRA levels in children.