bluuebunny/crossref_metadata_2025_split huggingface dataset:
O26 Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young Infants
Authors: Jacqz-Aigrain E , Leroux S , Thomson AH , Allegaert K , Capparelli EV , Biran V , Simon N , Meibohm B , Y-L Lo , Marqués R , Peris J-E , Lutsar I , Saito J , Nayamura H , van den Anker JN , Sharland M , Zhao W 
Published: May 2019

BackgroundIn the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.MethodsA ‘meta-model’ using NONMEM with 4894 concentrations from 1631 neonates was built and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming at reaching a target AUC0-24 of 400 mg*h/L at steady state in at least 80% of neonates.ResultsA two-compartment model best fitted the data. Current weight, post-menstrual age (PMA) and serum creatinine were the significant covariates for clearance (CL). After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg twice daily if < 35 weeks PMA and 15 mg/kg three times daily if ≥ 35 weeks PMA) achieved the AUC0-24 target earlier than a standard ‘Blue Book’ dosage regimen in more than 89% of the treated patients.ConclusionsThe results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and assist in the design of the model-based, multinational European trial, NeoVanc.Disclosure(s)Nothing to disclose
O27 Prospective evaluation of a population pharmacokinetic model of pantoprazole for obese children
Authors: Chapron A , Abdel-Rahman S , Shakhnovich V 
Published: May 2019

BackgroundPharmacokinetic (PK) data for proton pump inhibitors, acid suppressive medications commonly prescribed to children, are lacking for obese children who are at greatest risk for acid related disease. Our aim was to evaluate the performance of the only published population PK model of pantoprazole for obese children, in an independent cohort of obese and non-obese children.MethodsA published 2-compartment structural model,1 modified to exclude transit compartments for delayed absorption, was used to predict the PK of pantoprazole (PAN) oral suspension, immediate release (ka=7.3 hr-1). Calculated population parameters and covariate relationships (e.g., weight, CYP2C19 genotype) were extracted. Predictions were based on dose, sampling times, and covariates from 57 children (6–17 years; 21% obese, 28% overweight) who received a single dose PAN and had plasma PAN concentrations collected at 10 time-points over 8 hours. Model predictive performance was assessed visually and by relative root mean squared error (RMSE), with mean ratio of predicted-to-observed area under the concentration time curve (AUC) compared via one-way ANOVA across weight groups, defined by body mass index for age (10–84th percentile normal-weight, 85–94th percentile overweight, >95th percentile obese; α=0.05, R).ResultsThe model generally over-predicted observed PAN concentrations (RMSE 194%). Ratios of predicted versus observed AUC were not significantly different among obese, overweight and normal-weight children (1.5 vs. 1.7 vs. 2.2, p=0.06); however, a trend toward better model prediction was observed in the subset of obese children.ConclusionObserved PAN PK deviated from model predictions, which may be due to differences in patient demographics or PAN formulation. A validation study using a delayed release PAN formulation is in progress, with the overarching goal of understanding PAN disposition, and appropriate dose selection, for obese children, who are at potential risk for drug over- or under-dosing using commonly employed dosing strategies in pediatrics (e.g., mg/kg, weight-tiered).ReferencesShakhnovich, et al. A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents. Paediatr Drugs 2018 Oct;20(5):483–495.Disclosure(s)Nothing to disclose
O28 Variability in liver anatomy and physiology in children participating in pharmacokinetic studies
Authors: Friesen A , Radford J , Chan S , Mardis N , Shakhnovich V 
Published: May 2019

BackgroundObesity-related changes in liver anatomy and physiology (e.g., hepatic fat infiltration) may be important sources of interindivdual variability in hepatic drug metabolism and relevant covariates for physiologically-based pharmacokinetic (PBPK) models. The aim of this investigation was to quantify variability in hepatic fat fraction (HFF) and hepatic volume in children participating in PK studies, utilizing a novel, non-invasive, magnetic resonance imaging (MRI) sequence.1MethodsChildren, without a known diagnosis of fatty liver disease, enrolled in a PK study for hepatic CYP2C19 and CYP3A4 substrates, had hepatic volume and total HFF estimated using MRI proton density fat fraction (PDFF) and HFF assessed via conventional MRI spectroscopy (MRSFF) using a region of interest in the right upper hepatic lobe (LiverLab, Siemens Healthcare). Patient anthropometrics, laboratories and LiverLab outcomes were compared between obese and non-obese children, using independent student t-test, and associations explored via Spearman’s correlation (ρ); SPSSv24, α=0.05. Obesity was defined by body mass index (BMI)≥95th percentile for age; clinically significant liver adiposity defined as HFF>5%.Results25 children (7–20 years; 56% obese) had evaluable MRI data. Liver volume ranged 911–2227cm3, MRSFF 1.6–34.8% and PDFF 2.1–31.1%. Liver volume and HFF significantly correlated with BMI (both ρ=0.6, p< 0.01), but not age (both ρ=0.3, p>0.11). Liver volume (1574.5±367.1 vs 1284.8±216.3, p=0.04), MRSFF (8.9±8.4 vs 2.8±1.2, p=0.02), PDFF (8.9±7.0 vs 3.4±1.3, p=0.07) and alanine aminotransferase (ALT; 37.7±15.8 vs 26.8±3.6 IU/L, p=0.02) were higher in obese vs non-obese children. HFF>5% and ALT> 40 were only observed in obese children.ConclusionLiver volume and adiposity varied substantially among children and may be important covariates for pediatric PBPK models, especially for obese children. HFF> 5% and ALT> 40 were only observed in obese children. Recently, 24% reduction in clearance of azithromycin, a CYP3A4 substrate, was reported for children with ALT> 40.2 Our PK analyses are in progress.ReferencesCaussy C, Reeder SB, Sirlin CB, et al. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as as endpoint in NASH trials. Haptology 2018;68(2):763–72.Zheng Y, Liu SP, Xu BP, et al. Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia. Antimicrob Agents Chemother 2018;62 (9):e00686–18.Disclosure(s)Nothing to disclose
O32 Ontogeny of human kidney OCT2 expression across the paediatric age range
Authors: Smeets N , van Groen B , Pertijs J , Wilmer M , Smeets B , Verdijk R , de Wildt S 
Published: May 2019

BackgroundIn adults, the organic cation transporter 2 (protein name OCT2, gene name SLC22A2) is localised in the kidney proximal tubules where it mediates organic cation secretion. Hence, the transporter plays a role in the disposition and excretion of several drugs and drug-drug interactions. To better understand the disposition of OCT2 substrate drugs in children, we studied OCT2 localisation and expression in paediatric kidney tissue.MethodsThe expression of OCT2 was visualised in tissue using immunohistochemical staining. Tissues were derived post-mortem from children aged 0 -14 years. Gestational age varied between 24 and 40 weeks. Intensity of the staining at the basolateral membrane was scored by two individual observers using three categories; negative, detectible and high. Agreement between two observers was determined using Cohen’s kappa.Results44 kidney samples (n=17 neonates, n=17 infants, n=7 children, n=3 adolescent) were analysed and scored. There was substantial agreement between two judgements with a kappa of 0.773 (p< 0.005). No age related pattern was observed in the expression of OCT2. Even in the youngest age group, the expression of OCT2 was clearly visible.ConclusionThe kidney expression of OCT2 did not show an age-related pattern. In all age groups, expression levels were similar and OCT2 was properly localised at the basolateral membrane. These findings suggest that, with increasing age, OCT2 will not influence the renal excretion of its substrates.Disclosure(s)Nothing to disclose
O38 Population pharmacokinetics of ganciclovir after oral valganciclovir in renal transplant children
Authors: Facchin A , Elie V , Benyoub N , Baudouin V , Maisin A , Magreault S , Jacqz-Aigrain E 
Published: May 2019

BackgroundCytomegalovirus (CMV) infection is a major cause of morbidity in solid organ transplant recipients. Valganciclovir (ValG), prodrug of the antiviral ganciclovir, is used to prevent or treat CMV infection in this population. is controversial in children, As the percentage of patients reaching the pharmacological target is too low with currently used ValG dosing regimen, our aim was to determine ganciclovir population pharmacokinetics in renal transplant children receiving ValG and propose an appropriate dosage regimen.MethodsAfter transplantation, children receiving ValG were monitored for plasma ganciclovir concentrations using high performance liquid chromatography. Population pharmacockinetics analysis was performed with NONMEM.Results1212 samples from 104 renal transplant patients, aged 2 to 20 years, received ValG to prevent (n=80), treat (n=12), or both prevent then treat (n=12) CMV infection. ValG was administered orally at a daily dose of 19.8 ± 10.1 mg/kg (mean ± SD). A two-compartment model with first-order elimination best fitted the data. At steady-state, AUC24h-ss was 64.5 ± 23.4 µg/mL.h, apparent clearance (CL/F) was 0.39 ± 0.14 L/h/kg, apparent volume of distribution at steady-state (VDss/F) was 2.4 ± 0.48 L/kg. Ganciclovir CL/F increased with body surface area, decreased with increasing creatinine concentration and was 15% higher in boys. Central volume of distribution increased with body surface area (BSA) and showed a 14% increase in boys. Internal validation was performed.ConclusionWe have successfully built a pharmacokinetic model allowing to propose dosages adapted individually to the characteristics of renal transplanted children.Disclosure(s)Nothing to disclose
P02 Allopurinol counteracts inadequate mercaptopurine metabolism in paediatric acute lymphoblastic leukemia
Authors: Adam de Beaumais T , Petit A , Simonin M , Médard Y , Benchikh A , Dollfus C , Leverger G , Jacqz-Aigrain E 
Published: May 2019

BackgroundMercaptopurine (6-MP), a cornerstone of childhood acute lymphoblastic leukemia (ALL) therapy, is metabolized to active 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotides (6-MMPN) potentially hepatotoxic (threshold of 5000 pmol/8x108 RBC). In few cases, the equilibrium between 6-TGN and 6-MMPN is unbalanced and in favor to 6-MMPN with high risk of inefficacy and toxicities. Here, we treated patients with allopurinol which inhibits Xanthine Oxidase and Thiopurine S-methyl Transferase (TPMT) implicated in methylation of thiopurines.MethodsTherapeutic drug monitoring of ALL patients was based on the determination of metabolites concentrations in red blood cells, measured by HPLC-UV after 3 weeks of stable 6-MP dose. After parental consent, individual genotypes are determined for TPMT (*2, *3B, *3C), ITPA (c.94C>A) and HLA*B5801 (prior to allopurinol) by TaqMan allelic discrimination.ResultsIn 8 patients, 6-MMPN/6-TGN ratio was too high, superior to 50 (range: 58–248) with 6-TGN under therapeutic threshold (< 250 pmol/8x108 RBC). All patients have a wild-type TPMT genotype and for 3 patients, ITPA polymorphism could be involved to this disequilibrium. The co-administration of Allopurinol (50 mg n=5, 100 mg n=2), with a reduced 6-MP dose (around -50%) dose had a positive impact on metabolic ratio, inferior to 15 (range: < 1- 13) with metabolites levels inside therapeutic window and on resolving some toxicities (hypoglycemia (n=4), hepatotoxicity (n=3)). For one patient, 200 mg of Allopurinol was administered without reducing 6-MP dose, the metabolic ratio decreased from 115 to 63 but metabolites levels were both at supratherapeutic levels.ConclusionAllopurinol was effective in redirecting 6-MP metabolism to 6-TGN. A standardized protocol for this co-administration needs to be established and DNA-TGN incorporation dosage could be helpful for this recommendation. Long-term follow-up is required to evaluate impact on safety and efficacy of ALL maintenance therapy.Disclosure(s)Nothing to disclose
P03 Germline NUDT15 mutation and thiopurines for children with acute lymphoblastic leukemia: is it a prognostic factor?
Authors: Simonin M , Petit A , Médard Y , Benchikh A , Minckes O , Auvrignon A , Donadieu J , Leverger G , Jacqz-Aigrain E , Adam de Beaumais T 
Published: May 2019

BackgroundThe nudix hydrolase 15 (NUDT15) polymorphism recently emerges as a biomarker of severe hematological toxicity during 6-mercaptopurine (6-MP) therapy of children with acute lymphoblastic leukemia (ALL). Initially described restricted to Asian population, recent publications highlighted its presence in patients with European ancestry. In November 2018, the Clinical Pharmacogenetics Implementation Consortium (CPIC) updated the guideline for thiopurines dosing based on Thiopurine S-methyl transferase (TPMT) and NUDT15 genotypes. Here, we presented a feedback from a French monocentric experience in ALL patients.MethodsWe retrospectively genotyped 188 children for NUDT15 c.94C>A treated for ALL at Trousseau hospital, Paris. Parents have given their consent for thiopurines’ therapeutic drug monitoring including performing TPMT genotype (*2, *3B, *3C). We focused, for patients with a mutated NUDT15 genotype, on treatment response in terms of morbi-mortality.ResultsThis NUDT15 polymorphism was found for 6 patients (3.2%): one patient with a European ancestry and the others with an Asian ancestry. Five children had a NUDT15 mutated heterozygous genotype without TPMT alterations and one patient with a mutated homozygous NUDT15 genotype associated with TPMT *1/*3C. Hematological and/or infectious complications were reported for all patients with this variant with hospitalization in intensive care unit for the one with a mutated NUDT15 genotype and TPMT *1/*3C. Reduced 6-MP dose (between 30% to 50% of the standard dose for heterozygous patients and 3% of the standard dose for mutated homozygous patient) was required for maintenance therapy. Two patients had a relapse.ConclusionThis report supports CPIC guidelines for screening NUDT15 polymorphism before 6-MP treatment regardless patients‘ race. The impact of this polymorphism on relapse occurrence is worrying and prospective results with dose adjustments at 6-MP initiation will be crucial to understand if treatment interruptions and/or reduced dose were at risk of relapse.Disclosure(s)Nothing to disclose
P06 Paternal exposure to methotrexate and the risk of miscarriage – a register based nationwide cohort study
Authors: Andersen J , Askaa B , Jensen TB , Horwitz H , Vermehren C , Broedbaek K 
Published: May 2019

ObjectiveTo study the association between paternal exposure to methotrexate within three month before conception and during the first trimester of pregnancy and the risk of miscarriage.MethodsWe conducted a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2015. All births were identified using the Medical Birth Registry, and all records of induced abortion and miscarriage were from the National Hospital Register. Data on drug use were from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women with a partner exposed to methotrexate. The study was approved by the Danish Data Protection Agency (2015-41-4309).ResultsWe identified 1,364,063 registered pregnancies with known paternity, of whom 520 fathers were exposure to methotrexate within the three months before conception to the end of the first trimester. Among these, 46 (8.9%) experienced a miscarriage compared to 122,926 (9.0%) among the unexposed.There was no increased risk of experiencing a miscarriage in pregnancies to men exposed to methotrexate before pregnancy compared to unexposed (adjusted hazard ratio 0.99 (CI95% 0.67- 1.46)). Furthermore, we found no increased risk of experiencing a miscarriage in pregnancies to men exposed to methotrexate during first trimester compared to unexposed (adjusted hazard ratio 0.90 (CI95% 0.61–1.32)).ConclusionWe found no association between paternal exposure to methotrexate before and during early pregnancy and miscarriage. Available data suggest that paternal methotrexate exposure should not be of major concern. Multinational recommendations could be changed accordingly.Disclosure(s)Nothing to disclose
P08 Is there a difference in the frequency of manipulated orally and rectally administered medicines to paediatric in-patients in Sweden in the year 2009 and 2018 respectively? A register study
Authors: Andersson A , Eksborg S , Lindemalm S , Förberg U 
Published: May 2019

BackgroundSince there is a lack of drugs in suitable strengths and child-friendly dosage forms, manipulation is sometimes necessary in paediatrics. A manipulation is the physical alteration of a drug dosage form with the purpose to extract and administer the prescribed proportion of a drug dose.The purpose of this study was to calculate the frequency of manipulated medicines administered to paediatric in-patients at a large Children´s Hospital for two separate years and compare whether there has been a change in practice.Material and MethodsData were collected for all administered doses during 2 separate years (2009 and 2018) at the paediatric wards at our Children´s Hospital, from a hospital-based electronic register. All administered doses where the number of tablets or suppositories were decimal were added and calculated as a percentage of the total number of oral and rectal administrations. Data are anonymous but information regarding gender, age, hospital ward and number of drugs per patient were available and were analysed.ResultsIn one year, approximately 450 000 doses of medicine are administered to paediatric patients in our Children´s hospital.The results will be analysed with regards to differences between patient age, gender, prescribing year and drug substance. A pilot study showed that 10% of all solid oral administrations to patients 6 - 12 years old, were part of a tablet. For patients 0 - 2 years over 20% of all solid rectal administrations were part of a suppository.The extent of manipulation is affected by a lot of factors, where the most prominent is whether there are strengths suitable for that age-group available on the market or not.ConclusionMost often there is a lack of knowledge how manipulation of medicines influences the dosing accuracy and often we do this to our most vulnerable patients.Disclosure(s)Nothing to disclose
P09 Serum neurofilament light chain levels are an independent predictor of neurodevelopmental outcome in preterm infants
Authors: Hauck A , Goeral K , Atkinson A , Fuiko R , Leeb C , Michalak Z , Klebermass K , van den Anker J , Berger A , Kuhle J , Olischar M , Wellmann S 
Published: May 2019

Background and PurposeSerum neurofilament light chain (sNfL) has recently emerged as a promising biomarker reflecting structural neuro-axonal damage in different neurological diseases. Our study aimed at assessing whether sNfL can predict the functional outcome in preterm infants who suffered from neonatal haemorrhagic brain injury.MethodsIn this prospective observational study, we used an ultrasensitive single-molecule array assay to measure serum and cerebrospinal fluid (CSF) concentrations of NfL in preterm infants diagnosed with intraventricular haemorrhage (IVH) in the first few days of life. We determined the temporal profile of serum and CSF NfL levels from first diagnosis of IVH until term equivalent age, their association with cerebral imaging markers, and with clinical and functional outcome until 2 years of age assessed by Bayley Scales of Infant Development. We fitted univariable and multivariable logistic regression models to determine risk factors for low motor and cognitive development. Longitudinal mixed effects models modelled NfL levels using cubic spline smoothers to track the trajectory over time.ResultsThe study included 48 infants born with less than 32 weeks of gestation. At the time point of IVH diagnosis, NfL median levels were 271.9 pg/mL (IQR 151.2–389.7), and strongly decreased until term equivalent age to 15.7 pg/mL (IQR 11.1–32.2). CSF values were 113-fold higher (IQR 40–211) than corresponding serum values. Additional cerebral infarction (n=23) but not post-haemorrhagic hydrocephalus with permanent external ventricular drainage (n=29) or other diseases independently determined sNfL levels. In multivariate logistic regression models, the only significant predictor of poor motor outcome at 2 years or death was sNfL level (p=0.02).There was a clear difference between the NfL trajectory for those with poor motor outcome at 1 year.ConclusionsThis study shows that early sNfL is an independent prognostic biomarker for motor functional outcome in preterm infants after IVH.Disclosure(s)Nothing to disclose
P14 Pharmacovigilance in pediatric patients: the challenge of identifying new signal
Authors: Kronenfeld N , Gamsu S , Flor-Hirsch H , Agajani N , Sheinberg R , Ben-Nun L , Goldman M , Berkovitch M 
Published: May 2019

IntroductionThe importance of reporting adverse drug reactions (ADRs) is well known. However, the reporting rate is very low, and therefore, identifying new signal is challenging.ObjectiveTo create an interventional program in order to improve reporting rate and trying to identify new signal.Material and methodsThe interventional program was implemented at the Pediatric Division of Assaf Harofeh Medical Center and included presentations to the healthcare professionals, posters, creating new ADRs reporting methods and alerts.ResultsReporting rate of ADRs during the year before implementation of the program was negligible. During the study period (three months), the reporting rate increased dramatically. A new signal was reported; two neonates with apnea related to IVIG administration in the neonatology department. The distribution of reports was: 50% from the general pediatric department, 26% - pediatric neurology department, 21% and 6%, from the pediatric and neonatal intensive care units, respectively. Steroids and antibiotics were responsible for various ADRs, but not for a new signal.ConclusionThere is one case report in the literature on apnea related to IVIG administration. Adverse reactions in children are a major problem and sometimes can lead to morbidity mortality. Identifying new signal in pediatric patients is not common, and very challenging.Disclosure(s)Nothing to disclose