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IntroductionWith approximately 50% of the drugs being prescribed off-label, the pediatric population is in need for an innovative approach to establish harmonized, best evidence-based dosing guidelines. Physiologically-based pharmacokinetic (PBPK) modelling is a valuable approach to predict drug pharmacokinetics (PK) and to support dosing. As a first step to implement PBPK-informed dosing in pediatric clinical care, we aimed to identify drugs suitable to verify the PBPK approach and prioritize drugs in need of model-informed dosing.MethodsTo select a drug, it required to be listed on: 1. the Model List of Essential Medicines for Children (EMLc) of the WHO and on 2. the Dutch Pediatric Formulary (DPF). Also, a Simcyp® PBPK compound model had to be available. The level of evidence of the dosing recommendations in the DPF, the availability of pediatric pharmacokinetic data, and the opinion of clinicians on the relevance of the drug were reviewed for further prioritization.ResultsOf all drugs on the EMLc, 199 are listed in the DPF. For 76 of them, a Simcyp® compound model is available, either directly in the software, its repository, or from scientific literature. Eleven drugs have sufficient PK data to verify the PBPK modeling approach. For 48 drugs, we identify a moderate to high priority for a model-informed dose.ConclusionsThis work now provides input for the next steps which include verification of PBPK model performance in pediatrics and subsequent PBPK modelling to establish dosing guidelines. A joint effort and an internationally accessible platform are needed to share information on pediatric PBPK modelling to eventually implement model-informed doses in clinical practice.This abstract is based on research funded by the Bill & Melinda Gates Foundation

IntroductionMedicines are becoming increasingly common for all populations and polypharmacy has been shown to have numerous risks. Although primary studies and reviews have explored the impact of medical conditions on patients and caregivers, there are no known reviews on the impact of medicines on paediatric patients. This systematic review therefore aimed to determine the domains commonly assessed in studies assessing treatment burden in different conditions for paediatric patients and their caregivers.MethodsSearches were conducted on Medline, CINAHL, EMBASE, Web of Science and Cochrane Database of Systematic Reviews to find relevant papers. Two reviewers independently screened the papers based on the chosen inclusion and exclusion criteria. The quality of the papers was assessed independently by two reviewers using the Newcastle Ottawa Scale. This review was registered with PROSPERO (PROSPERO registration number: CRD42021285097) and conducted according to PRISMA methodology.Results6 papers with 8276 participants were identified in this review. The domains most commonly assessed were the perceived effectiveness of medications (4/6 studies), psychosocial impact (3/6 studies) and the impact on work and school (3/6 studies). Other domains included the ease of use of medicines, side effects from medicines, adherence to medicines, time requirements, costs, using healthcare resources and support from family/friends/organisations.ConclusionsStudies assessing the burden of care due to medicines assessed a range of domains related to the impact of medicines on patients and caregivers. The results from this review will be used create a questionnaire for a cohort study that aims to determine the impact of polypharmacy on paediatric patients and their parents.

IntroductionMucopolysaccharidoses (MPS), comprise a group of rare chronically debilitating metabolic diseases and associated with reduced life expectancy and a substantial unmet clinical need. Current research directs towards a number of new treatment targets and strategies. Individual treatment trials (ITT) could make these options rapidly available to patients. Based on scientific publication, this is hardly used. We assess the utilization of and relevant barriers to ITT in MPS as well as potential solutions.MethodsPhase 1 was done with 5 international top experts. After this interim analysis, the survey will be rolled out to a broader group of experts.ResultsFive MPS experts from Austria, Brazil, Germany and Italy have been enrolled. In total these clinicians manage about 350 MPS patients. Only three experts ever ran 1–3 numbers of ITT in MPS patients, solely MPS type II (n=2) and VI (n=1), summing up to a total of five ITTs, which is about 1.4% of their patients. The treatments used in ITTs comprise Montelukast, THC, Curcuma and a viral vector with transgene. As barriers for a wider use of ITTs, the im-practicability for implementation (n=1) and the insufficient training in ITT (n=1) have been indicated. All experts consider it highly likely that a decision analysis tool increases the use of ITT in MPS.ConclusionsITT are used in about 1% of MPS patients. This seems extremely low, considering the commonness of off label use in children with severe conditions, the high unmet medical need in MPS and the number of research results, which indicate various promising repurposing strategies. This interim analysis already demonstrates several relevant barriers and high potential of the planned decision framework tool to overcome this.

IntroductionWe sought to detect a relationship between midazolam concentration and development of new delirium in critically ill children who were on continuous midazolam administration.MethodsDelirium was detected using the Sophia Observation withdrawal Symptoms - Paediatric Delirium (SOS-PD) score and 104 left-over samples were available to measure midazolam concentrations.ResultsTwenty-five percent of the included patients developed new delirium. Median cumulative midazolam dose was higher in patients who developed delirium compared to those without delirium but lower compared with the day preceding delirium detection, indicative of a rapid decline. Similar findings were made when active metabolites 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide were considered.ConclusionsA sudden and significant reduction in midazolam concentration may contribute to the development of a delirium in critically ill children.

IntroductionEvidence-based (EB) data on various medicaments and safe drug dosing in pediatric population are already available across Europe. However, their systematic translation and clear processing are lacking in daily pediatric clinical practice in the Czech Republic. The purpose of our work is the development of a Czech drug database similar to some already existing internationally based formulary lists.MethodsA systematic approach to the processing of recommended dosages of drugs used in the Czech environment, all compiled in the Czech language. The active substances will be arranged according to the ATC classification system. The strategy of the initial focus on the most commonly used drugs is set (the statistical data will be obtained from SÚKL), more rarely used drugs will be approached subsequently. The server-side system will be based on PHP and MySQL technologies, enabling easy scalability and deployment to a wide range of servers, including the ability to deploy to scalable servers with a load balancer front-end server.ResultsIn 2022, the Czech team managed to obtain support for the creation of a database called Gama 2 project TP01010040, supported by The Centre for Knowledge and Technology Transfer of Charles University (EudraCT#). As expected, the database will be developed in the most appropriate data processing framework and validated throughout the year.ConclusionsThe Gama 2 database project aims to extrapolate strictly EB data systematically processed according to ATC groups into the Czech environment, where it will become a unique reference for safe prescribing, dispensing and administration of drugs in pediatric population. When processed in the Czech language, this might be beneficial for healthcare providers in Czech medical facilities.

IntroductionIncreasingly, hospitals rely on local clinical practice guidelines (CPGs) alongside national guidance to standardise clinical care. This study examines variation between national and local CPGs, using the example of acute paediatric asthma (APA) CPGs from the United Kingdom and the Netherlands.MethodsFifteen British and Dutch local CPGs were collected with the matching national guidance for the management of APA. The drug sequences, routes and methods of administration recommended for patients with severe APA were represented. Deviations from national guidance were measured. Variation in recommended doses of intravenous salbutamol was examined. CPG quality was assessed using the AGREE II instrument.ResultsBritish and Dutch national CPGs differed in the recommended drug choices, sequences, routes and methods of administration for severe APA. Local British CPGs diverged from national guidance for 23% of their recommended interventions compared to 8% for Dutch local CPGs. Variation in second-line recommendations was greater than for first-line recommendations across local CPGs from both countries. Recommended starting doses for salbutamol infusions varied by more than tenfold. The quality of the sampled local CPGs was low across five out of six AGREE domains (<60%).ConclusionsLocal CPGs for the management of severe APA featured substantial variation and frequently diverged from national guidance. Their methodological quality was low. Although limited to one condition, this study suggests that unmeasured variation across local CPGs may contribute to variation of care more broadly, potentially undermining healthcare quality.

IntroductionIncreased plasma renin activity (PRA) levels may have various causes: PRA has gained importance as prognostic marker for patients with heart failure; age may have an influence on endogenous PRA levels; and ACE inhibitor (ACEi) treatment can also interfere with PRA levels. We aimed to investigate PRA levels in very young children with heart failure, with and without ACEi treatment.MethodsAs part of a PK-PD study of enalapril for pediatric heart failure (LENA studies), blood samples were collected and analyzed for PRA levels before, 4 hours after and within the first week of enalapril treatment. In addition, a literature search was conducted according to the PRISMA concept in MEDLINE to identify studies on PRA levels in healthy children as well as in children with heart failure in the age range from 1 day up to 2 years. Comparison was performed with LENA study data and with data from 9 healthy volunteers.ResultsInfants from LENA studies with heart failure (n= 35, aged 25 days – 2.1 years) had median PRA levels of 19.7 (n=35) before, 29.0 (n=34, p>0.05) 4 hours after enalapril dose, and 89.1 ng/mL/h (n=29, p<0.01) after 5 days of treatment. Literature search revealed mean PRA levels in healthy children between 2.3 to 29.8 (n= 14 studies) and 10.0 to 87.1 ng/mL/h in ACEi naïve heart failure children (n= 4 studies). PRA levels of 9 healthy adults ranged between 0.13 to 1.85 ng/mL/h.ConclusionsVery young children had higher endogenous PRA levels compared to adults. Heart failure at this age was associated with even higher PRA levels and ACEi treatment further increased PRA levels. These results indicate that patients appear to respond to ACEi treatment but question the value of PRA levels as prognostic marker in this population.

Measuring concentrations of paracetamol could be a strategy to optimize the treatment of pain. It is not known if the serum trough concentration of paracetamol at steady state conditions could predict a decrease in pain scores in preterm and term neonates. Low trough concentration can result in inadequate pain relief. The aim of this study was to determine the association between the serum trough concentration of paracetamol and pain reduction in preterm and term neonates.In this retrospective observational study a hospital database was used to select neonates who were treated with at least 48 hours of paracetamol intravenously or rectally. Linear regression was performed to determine if serum trough concentration of paracetamol at steady state conditions was a predictor for pain reduction. Pain reduction was defined as the difference between COMFORTneo scores before administration and after the fifth administration of paracetamol.21 neonates were included for determining the association between serum trough concentration paracetamol and pain reduction. The median (IQR) of serum trough concentration of paracetamol after the fifth dose was 4.5 mg/L (2.7–8.5 mg/L). At steady state conditions the serum trough concentration of paracetamol was not a significant predictor of pain reduction in preterm and term neonates (p = 0.79 for preterm neonates and p = 0.49 for term neonates).No association was found between the serum trough concentration of paracetamol at steady state conditions and pain reduction in preterm and term neonates. The absence of a significant association could be due to inadequate trough concentrations paracetamol. Further research is needed to investigate the association between serum trough concentrations paracetamol of ≥ 10 mg/L and pain reduction.

IntroductionCurrent guidelines recommend step-down of asthma drugs once stable asthma has been achieved but there is no guidance regarding deprescribing long acting beta2 agonists (LABAs) in the paediatric population.AimTo systematically review evidence regarding deprescribing methods of LABAs in the paediatric population.MethodsSearches were undertaken in the following databases: EMBASE, Medline, PubMed and CINAHL regarding reports of deprescription or discontinuation of LABAs in children and adolescents with persistent asthma.ResultsThe search returned 168 papers following deduplication. 4 papers met the eligibility criteria including 3 randomised control trials and 1 retrospective study. Overall, LABA step down was attempted in 365 children and young people (5–18 years old). The studies had variable follow up durations once deprescribing was undertaken, from 2 to 12 weeks. Effects of withdrawal were measured using parameters such as airway hyperresponsiveness tests (3 studies), asthma control test scores (3 studies), use of rescue medication (3 studies) and lung function tests (FeNO, FEV1, FEF25–75%, peak expiratory flow rate (PEFR),% forced expiratory flow at 50% of vital capacity (%V50)) (all studies). Airway responsiveness was unchanged 2 weeks following LABA withdrawal, however decreases in%PEFR and%V50, FEV1 and asthma control test scores were observed. 2 studies assessed changes in LABA related adverse effects after deprescribing.ConclusionThere is limited and short-term evidence regarding stepping down LABAs in paediatrics. To fully implement national and international guidelines, prospective studies in this area are required.

IntroductionOff-label use is still inevitable for paediatric drug treatment. The aim of this study was to analyse the licensing status of drug prescriptions in German paediatric (specialised) outpatient clinics and to determine changes over a 10-year time course.MethodsCross-sectional, retrospective, monocentric studies were conducted in 2009 and 2019 to assess drug prescriptions regarding their licensing status in 10 (one general and nine specialised) outpatient clinics in Germany. Prevalence and relative frequency of off-label prescriptions were calculated, reasons for off-label prescribing analysed and logistic regression performed to determine influencing factors.Results751 prescriptions of 296 patients in 2009 and 1438 prescriptions of 786 patients in 2019 were examined and classified according to their licensing status. Relative frequency of off-label prescriptions was around 45% without significant change over that decade. Prevalence of off-label prescriptions was 60.1% in 2009 and 53.1% in 2019 and therefore significantly higher in 2009 (p=0.037). The number of prescriptions per patient was significantly higher in 2009 (2.5 ± 2.3 vs. 1.8 ± 1.5, p<0.000), too. Comparison revealed the same high-ranking reasons in every study: off-label use due to indication, overdosing and missing paediatric information.ConclusionsOff-label prescribing still plays an important role in clinical daily routine in paediatrics. Despite numerous regulatory efforts and incentives, no substantial reduction in off-label prescribing could be determined since 2009. Further efforts are needed to generate more evidence-based knowledge about paediatric pharmacotherapy and to treat children as best as possible.