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. Bioconversion of midazolam, a CYP3A4/5 model substrate, was studied using enteroid monolayers as well as tissue explants in the Ussing chamber, both derived from pediatric [median (range age): 54 weeks (2 days - 13 years), n = 21] and adult (n = 5) tissue. Caco-2 cellular monolayers were employed as controls. In addition, mRNA expression of CYP3A4 was determined in enteroid monolayers (n = 11), tissue (n = 23) and Caco-2 using RT-qPCR. Midazolam metabolism was successfully detected in all enteroid monolayers, as well as in all tissue explants studied in the Ussing chamber, whereas Caco-2 showed no significant metabolite formation. The extracted fraction of midazolam was similar between enteroid monolayers and tissue. The fraction of midazolam extracted increased with age in enteroid monolayers derived from 0 to 70 week old donors. No statistically significant correlation was observed in tissue likely due to high variability observed and the smaller donor numbers included in the study. At the level of gene expression, CYP3A4 increased with age in tissues (n = 32), while this was not reflected in enteroid monolayers (n = 16). Notably, asymmetric metabolite formation was observed in enteroids and tissue, with higher metabolite formation on the luminal side of the barrier. In summary, we demonstrated that enteroids can be used to measure CYP3A4/5 midazolam metabolism, which we show is similar as observed in fresh isolated tissue. This was the case both in children and adults, indicating the potential of enteroids to predict intestinal metabolism. This study provides promising data to further develop enteroids to study drug metabolism in vitro and potentially predict oral absorption for special populations as an alternative to using fresh tissue.

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. Physiologically-based pharmacokinetic (PBPK) models can be used to design individualized dosing regimens taking this into account. Dexamethasone, prescribed for the prevention post-extubation stridor (PES), is metabolized by the drug metabolizing enzyme CYP3A. As CYP3A4 undergoes major changes during childhood, we aimed to develop age-appropriate dosing recommendations for children of dexamethasone for PES, as proof of concept for PBPK modeling to individualize dosing for critically ill patients. Methods: All simulations were conducted in Simcyp™ v21 (a population-based PBPK modeling platform), using an available dexamethasone compound model and pediatric population model in which CYP3A4 ontogeny is incorporated. Published pharmacokinetic (PK) data was used for model verification. Evidence for the dose to prevent post-extubation stridor was strongest for 2-6 year old children, hence simulated drug concentrations resulting from this dose from this age group were targeted when simulating age-appropriate doses for the whole pediatric age range. Results: Dexamethasone plasma concentrations upon single and multiple intravenous administration were predicted adequately across the pediatric age range. Exposure-matched predictions of dexamethasone PK indicated that doses (in mg/kg) for the 2-6 years olds can be applied in 3 month-2 year old children, whereas lower doses are needed in children of other age groups (60% lower for 0-2 weeks, 40% lower for 2-4 weeks, 20% lower for 1-3 months, 20% lower for 6-12 year olds, 40% lower for 12-18 years olds). Discussion: We show that PBPK modeling is a valuable tool that can be used to develop model-informed recommendations using dexamethasone to prevent PES in children. Based on exposure matching, the dose of dexamethasone should be reduced compared to commonly used doses, in infants <3 months and children ≥6 years, reflecting age-related variation in drug disposition. PBPK modeling is an promising tool to optimize dosing of critically ill patients.

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. Given historically limited data, pharmacokinetic models may inform pregnancy-adjusted doses. However, implementing model-informed doses in clinical practice requires support from relevant stakeholders. PURPOSE: To explore the perceived barriers and facilitators for model-informed antenatal doses among healthcare practitioners (HCPs) and pregnant women. METHODS: Online focus groups and interviews were held among healthcare practitioners (HCPs) and pregnant women from eight countries across Europe, Africa and Asia. Purposive sampling was used to identify pregnant women plus HCPs across various specialties prescribing or providing advice on medication to pregnant women. Perceived barriers and facilitators for implementing model-informed doses in pregnancy were identified and categorised using a hybrid thematic analysis. RESULTS: Fifty HCPs and 11 pregnant women participated in 12 focus groups and 16 interviews between January 2022 and March 2023. HCPs worked in the Netherlands (n = 32), the UK (n = 7), South Africa (n = 5), Uganda (n = 4), Kenya, Cameroon, India and Vietnam (n = 1 each). All pregnant women resided in the Netherlands. Barriers and facilitators identified by HCPs spanned 14 categories across four domains whereas pregnant women described barriers and facilitators spanning nine categories within the same domains. Most participants found current antenatal dosing information inadequate and regarded model-informed doses in pregnancy as a valuable and for some, much-needed addition to antenatal care. Although willingness-to-follow model-informed antenatal doses was high across both groups, several barriers for implementation were identified. HCPs underlined the need for transparent model validation and endorsement of the methodology by recognised institutions. Foetal safety was deemed a critical knowledge gap by both groups. HCPs' information needs and preferred features for model-informed doses in pregnancy varied. Several pregnant women expressed a desire to access information and partake in decisions on antenatal dosing. CONCLUSIONS: Given the perceived limitations of current pharmacotherapy for pregnant women and foetuses, model-informed dosing in pregnancy was seen as a promising means to enhance antenatal care by pregnant women and healthcare practitioners.

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. This study aims to describe the clinical management of this interaction, based on a case series and review of literature. METHODS: Four individuals with childhood-onset CNS disorders (age 8-24) and CNS-depressant overdose symptoms after the concomitant use of ITB and opioids are described. The Drug Interaction Probability Scale (DIPS) was calculated to assess the cause-relationship (doubtful <2, possible 2-4, probable 5-8, and highly probable >8) of the potential drug-drug interaction. A literature review of similar previously reported cases and the possible pharmacological mechanisms of opioid-baclofen interaction is provided. RESULTS: After ITB and opioid co-administration, three out of four patients had decreased consciousness, and three developed respiratory depression. DIPS scores indicated a possible cause-relationship in one patient (DIPS: 4) and a probable cause-relationship in the others (DIPS: 6, 6, and 8). Discontinuation or adjusting ITB or opioid dosages resulted in clinical recovery. All patients recovered completely. In the literature, two articles describing nine unique cases were found. CONCLUSION: Although the opioid-ITB interaction is incompletely understood, concomitant use may enhance the risk of symptoms of CNS-depressant overdose, which are potentially life-threatening. If concomitant use is desirable, we strongly recommend to closely monitor these patients to detect interaction symptoms early. Awareness and monitoring of the potential opioid-ITB interaction is essential to reduce the risk of severe complications.

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. Data from nonhuman primates and sheep suggest maintaining a fetal plasma concentration above 1 ng/mL for 48 hours to retain efficacy, while avoiding undesirable high fetal plasma levels. OBJECTIVE: We aimed to re-evaluate the current betamethasone and dexamethasone dosing strategies to assess estimated fetal exposure and provide new dosing proposals that meet the efficacy target but avoid excessive peak exposures. STUDY DESIGN: A pregnancy physiologically based pharmacokinetic (PBPK) model was used to predict fetal drug exposures. To allow prediction of the extent of betamethasone and dexamethasone exposure in the fetus, placenta perfusion experiments were conducted to determine placental transfer. Placental transfer rates were integrated in the PBPK model to predict fetal exposure and model performance was verified using published maternal and fetal pharmacokinetic data. The verified pregnancy PBPK models were then used to simulate alternative dosing regimens to establish a model-informed dose. RESULTS: Ex vivo data showed that both drugs extensively cross the placenta. For betamethasone 15.7±1.7% and for dexamethasone 14.4±1.5%, the initial maternal perfusate concentration reached the fetal circulations at the end of the 3-hour perfusion period. Pregnancy PBPK models that include these ex vivo-derived placental transfer rates accurately predicted maternal and fetal exposures resulting from current dosing regimens. The dose simulations suggest that for betamethasone intramuscular, a dose reduction from 2 dosages 11.4 mg, 24 hours apart, to 4 dosages 1.425 mg, 12 hours apart would avoid excessive peak exposures and still meet the fetal response threshold. For dexamethasone, the dose may be reduced from 4 times 6 mg every 12 hours to 8 times 1.5 mg every 6 hours. CONCLUSION: A combined placenta perfusion and pregnancy PBPK modeling approach adequately predicted both maternal and fetal drug exposures of 2 antenatal corticosteroids (ACSs). Strikingly, our PBPK simulations suggest that drug doses might be reduced drastically to still meet earlier proposed efficacy targets and minimize peak exposures. We propose the provided model-informed dosing regimens are used to support further discussion on an updated ACS scheme and design of clinical trials to confirm the effectiveness and safety of lower doses.

Intermittent intravenous paracetamol versus continuous morphine in infants undergoing cardiothoracic surgery: a multi-center randomized controlled trial.

BACKGROUND: To determine whether intermittent intravenous (IV) paracetamol as primary analgesic would significantly reduce morphine consumption in children aged 0-3 years after cardiac surgery with cardiopulmonary bypass. METHODS: Multi-center, randomized, double-blinded, controlled trial in four level-3 Pediatric Intensive Care Units (PICU) in the Netherlands and Belgium. Inclusion period; March 2016-July 2020. Children aged 0-3 years, undergoing cardiac surgery with cardiopulmonary bypass were eligible. Patients were randomized to continuous morphine or intermittent IV paracetamol as primary analgesic after a loading dose of 100 mcg/kg morphine was administered at the end of surgery. Rescue morphine was given if numeric rating scale (NRS) pain scores exceeded predetermined cutoff values. Primary outcome was median weight-adjusted cumulative morphine dose in mcg/kg in the first 48 h postoperative. For the comparison of the primary outcome between groups, the nonparametric Van Elteren test with stratification by center was used. For comparison of the proportion of patients with one or more NRS pain scores of 4 and higher between the two groups, a non-inferiority analysis was performed using a non-inferiority margin of 20%. RESULTS: In total, 828 were screened and finally 208 patients were included; parents of 315 patients did not give consent and 305 were excluded for various reasons. Fourteen of the enrolled 208 children were withdrawn from the study before start of study medication leaving 194 patients for final analysis. One hundred and two patients received intermittent IV paracetamol, 106 received continuous morphine. The median weight-adjusted cumulative morphine consumption in the first 48 h postoperative in the IV paracetamol group was 5 times lower (79%) than that in the morphine group (median, 145.0 (IQR, 115.0-432.5) mcg/kg vs 692.6 (IQR, 532.7-856.1) mcg/kg; P < 0.001). The rescue morphine consumption was similar between the groups (p = 0.38). Non-inferiority of IV paracetamol administration in terms of NRS pain scores was proven; difference in proportion - 3.1% (95% CI - 16.6-10.3%). CONCLUSIONS: In children aged 0-3 years undergoing cardiac surgery, use of intermittent IV paracetamol reduces the median weight-adjusted cumulative morphine consumption in the first 48 h after surgery by 79% with equal pain relief showing equipoise for IV paracetamol as primary analgesic. Trial Registration Clinicaltrials.gov, Identifier: NCT05853263; EudraCT Number: 2015-001835-20.

[Adequate medication doses for pregnant women and their unborn children]. / Gepaste medicatiedoseringen voor zwangere en foetus.

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. However, in the face of scarce evidence, such doses are generally lacking, potentially contributing to an increased risk of treatment failure or toxicity in pregnant women and their unborn children. By integrating physiological and/or population data, pharmacokinetic models can be used to determine appropriate medication dosages among pregnant women and their unborn children, as well as other patient groups for which evidence-based doses may be lacking such as children, elderly or obese patients. In order to translate model predictions into clinically usable doses, a number of conditions must be met, including careful model validation, an assessment of evidence from pharmacokinetic modelling alongside available clinical studies by multidisciplinary experts, as well as transparent communication towards end-users on the considerations for determining appropriate medication doses.

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. We aim to bridge this gap and propose the use of a confidence interval for the predicted-to-observed geometric mean ratio with predefined boundaries. This approach is similar to currently accepted bioequivalence testing procedures and can aid in improved model credibility and acceptance. METHODS: Two different methods to construct a confidence interval are outlined, depending on whether individual observations or aggregate data are available from the clinical comparator data sets. The two testing procedures are demonstrated for an example evaluation of a midazolam PBPK model. In addition, a simulation study is performed to demonstrate the difference between the twofold criterion and our proposed method. RESULTS: Using midazolam adult pharmacokinetic data, we demonstrated that creating a confidence interval yields more robust evaluation of the model than a point estimate, such as the commonly used twofold acceptance criterion. Additionally, we showed that the use of individual predictions can reduce the number of required test subjects. Furthermore, an easy-to-implement software tool was developed and is provided to make our proposed method more accessible. CONCLUSIONS: With this method, we aim to provide a tool to further increase confidence in PBPK model performance and facilitate its use for directly informing drug dosing in clinical care.

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. Outcomes: Prevalence of chronic postsurgical pain (CPSP) one year after scoliosis surgery and postsurgical pain course during this year. The need for rescue medication and the relationship between pre-operative T-QST, acute pain and CPSP. Results: Thirty-nine patients (mean age 13.9 years; SD 1.9 years) completed the study. One year postoperatively, ten patients (26%) self-reported pain [numeric rating scale (NRS) score ≥ 4]) when moving and two (5%) when in rest. Four of these patients (10.3%) experienced neuropathic pain. The pre-operative cold pain threshold was lower (p = 0.002) in patients with CPSP at 12 months. Preoperative cold and heat pain thresholds were correlated with the number of moderate or severe pain reports (NRS ≥ 4) in the first week postoperatively (r -.426; p = 0.009 and r.392; p = 0.016, respectively). Conclusions: One year after scoliosis surgery, a significant part of patients (26%) still reported pain, some with neuropathic characteristics. Better diagnosis and treatment is needed; our study suggests that T-QST could be further explored to better understand and treat children with this negative outcome.

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. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Maximum likelihood estimation of renal transporter ontogeny profiles for pediatric PBPK modeling.

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 for RT activity in children, especially neonates, to predict drug disposition. Therefore, RT expression measurements from human kidney postmortem cortical tissue samples were normalized to represent a fraction of mature RT activity. Using these data, maximum likelihood estimated the distributions of RT activity across the pediatric age spectrum, including preterm and term neonates. PBPK models of four RT substrates (acyclovir, ciprofloxacin, furosemide, and meropenem) were evaluated with and without ontogeny profiles using average fold error (AFE), absolute average fold error (AAFE), and proportion of observations within the 5-95% prediction interval. Novel maximum likelihood profiles estimated ontogeny distributions for the following RT: OAT1, OAT3, OCT2, P-gp, URAT1, BCRP, MATE1, MRP2, MRP4, and MATE-2 K. Profiles for OAT3, P-gp, and MATE1 improved infant furosemide and neonate meropenem PBPK model AFE from 0.08 to 0.70 and 0.53 to 1.34 and model AAFE from 12.08 to 1.44 and 2.09 to 1.36, respectively, and improved the percent of data within the 5-95% prediction interval from 48% to 98% for neonatal ciprofloxacin simulations, respectively. Even after accounting for other critical population-specific maturational differences, novel RT ontogeny profiles substantially improved neonatal PBPK model performance, providing validated estimates of maturational differences in RT activity for optimal dosing in children.

Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept.

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 and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation. Methods: An already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios. After acceptance of the model, dosages now recommended by the Dutch Pediatric Formulary (DPF) were simulated, along with several alternative dosing scenarios, aiming for recommended peak (i.e., 8-12 mg/L for neonates and 15-20 mg/L for infants) and trough (i.e., <1 mg/L) levels. We then used a decision framework to weigh benefits and risks for implementation. Results: The PBPK model adequately described gentamicin PK. Simulations of current DPF dosages showed that the dosing interval for term neonates up to 6 weeks of age should be extended to 36-48 h to reach trough levels <1 mg/L. For infants, a 7.5 mg/kg/24 h dose will reach adequate peak levels. The benefits of these dose adaptations outweigh remaining uncertainties which can be minimized by routine drug monitoring. Conclusion: We used a PBPK model to show that current DPF dosages for gentamicin in term neonates and infants needed to be optimized. In the context of potential uncertainties, the risk-benefit analysis proved positive; the model-informed dose is ready for clinical implementation.

Physiologically-Based Pharmacokinetic Modeling for Drug Dosing in Pediatric Patients: A Tutorial for a Pragmatic Approach in Clinical Care.

It is well-accepted that off-label drug dosing recommendations for pediatric patients should be based on the best available evidence. However, the available traditional evidence is often low. To bridge this gap, physiologically-based pharmacokinetic (PBPK) modeling is a scientifically well-founded tool that can be used to enable model-informed dosing (MID) recommendations in children in clinical practice. In this tutorial, we provide a pragmatic, PBPK-based pediatric modeling workflow. For this approach to be successfully implemented in pediatric clinical practice, a thorough understanding of the model assumptions and limitations is required. More importantly, careful evaluation of an MID approach within the context of overall benefits and the potential risks is crucial. The tutorial is aimed to help modelers, researchers, and clinicians, to effectively use PBPK simulations to support pediatric drug dosing.

Prognostic Factors for Long-term Aesthetic Outcome of Infantile Haemangioma Treated with Beta-blockers.

Parents of infants treated with beta-blockers for infantile haemangioma are often concerned about the long-term aesthetic outcome. This cross-sectional study assessed the influence on the long-term aesthetic outcome of characteristics of the infantile haemangioma, the beta-blocker treatment, and the infant. The study included 103 children aged 6-12 years, treated with beta-blockers (propranolol or atenolol) for infantile haemangioma during infancy (age at treatment initiation ≤1 year) for ≥6 months. Dermatologists and parents scored the Patient Observer Scar Assessment Scale, and the child scored a visual analogue scale. Dermatologists identified whether telangiectasia, fibrofatty tissue, and atrophic scar tissue were present. The long-term aesthetic outcome of infantile haemangioma was judged more negatively by dermatologists and parents in case of a superficial component, ulceration, older age at treatment initiation, higher cumulative dose, and/or shorter follow-up time. According to children, infantile haemangioma located on the head had better aesthetic outcome than infantile haemangioma located elsewhere. Close monitoring, particularly of infantile haemangioma with a superficial component, is essential for early initiation of treatment, and to prevent or treat ulceration. These outcome data can support parental counselling and guide treatment strategy.

Optimizing expert and patient input in pediatric trial design: Lessons learned and recommendations from a collaboration between conect4children and European Patient-CEntric ClinicAl TRial PLatforms.

Advice from multiple stakeholders is required to design the optimal pediatric clinical trial. We present recommendations for acquiring advice from trial experts and patients/caregivers, derived from advice meetings that were performed through a collaboration of the Collaborative Network for European Clinical Trials for Children (c4c) and the European Patient-CEntric ClinicAl TRial PLatforms (EU-PEARL). Three advice meetings were performed: (1) an advice meeting for clinical and methodology experts, (2) an advice meeting for patients/caregivers, and (3) a combined meeting with both experts and patients/caregivers. Trial experts were recruited from c4c database. Patients/caregivers were recruited through a patient organization. Participants were asked to provide input on a trial protocol, including endpoints, outcomes, and the assessment schedule. Ten experts, 10 patients, and 13 caregivers participated. The advice meetings resulted in modification of eligibility criteria and outcome measures. We have provided recommendations for the most effective meeting type per protocol topic. Topics with limited options for patient input were most efficiently discussed in expert advice meetings. Other topics benefit from patient/caregiver input, either through a combined meeting with experts or a patients/caregivers-only advice meeting. Some topics, such as endpoints and outcome measures, are suitable for all meeting types. Combined sessions profit from synergy between experts and patients/caregivers, balancing input on protocol scientific feasibility and acceptability. Both experts and patients/caregivers provided critical input on the presented protocol. The combined meeting was the most effective methodology for most protocol topics. The presented methodology can be used effectively to acquire expert and patient feedback.

Global Association of the COVID-19 Pandemic With Pediatric Clinical Trial Publication.

This cross-sectional study investigates the association of the COVID-19 pandemic with rates of pediatric clinical trial publication.

Neonatal Drug Formularies-A Global Scope.

Neonatal drug information (DI) is essential for safe and effective pharmacotherapy in (pre)term neonates. Such information is usually absent from drug labels, making formularies a crucial part of the neonatal clinician's toolbox. Several formularies exist worldwide, but they have never been fully mapped or compared for content, structure and workflow. The objective of this review was to identify neonatal formularies, explore (dis)similarities, and raise awareness of their existence. Neonatal formularies were identified through self-acquaintance, experts and structured search. A questionnaire was sent to all identified formularies to provide details on formulary function. An original extraction tool was employed to collect DI from the formularies on the 10 most commonly used drugs in pre(term) neonates. Eight different neonatal formularies were identified worldwide (Europe, USA, Australia-New Zealand, Middle East). Six responded to the questionnaire and were compared for structure and content. Each formulary has its own workflow, monograph template and style, and update routine. Focus on certain aspects of DI also varies, as well as the type of initiative and funding. Clinicians should be aware of the various formularies available and their differences in characteristics and content to use them properly for the benefit of their patients.