bluuebunny/crossref_metadata_2025_split huggingface dataset:
O16 Piglets as animal model to assess the contribution of fluid therapy to the development of augmented renal clearance in children
Authors: Dhondt L , Croubels S , De Paepe P , De Cock P , Devreese M 
Published: May 2019

BackgroundThe past years augmented renal clearance (ARC), observed in the critically ill paediatric population, has received an increased attention by researchers due to its major impact on drug exposure.1 Since a recent report demonstrated that the maturation of the glomerular filtration rate (GFR) in juvenile pigs is comparable to children, pigs may be a potential animal model to investigate the impact and mechanisms of ARC on drug pharmacokinetics (PK) in children.2In this pilot study, the contribution of intravenous (IV) fluid administration on the development of ARC was investigated in piglets.MethodsEight seven-week-old pigs underwent an experiment without fluid therapy and two consecutive fluid treatments as CRI of a 0.9% NaCl solution (3 mL/kg/h and 6 mL/kg/h) over 36 hours, each time combined with IV administration of a cocktail of renal markers after 4 and 24 h of fluid administration. This cocktail consisted of iohexol (64.7 mg/kg body weight (BW), Omnipaque 300®, marker for GFR) and para-aminohippuric acid (10 mg/kg BW, marker for effective renal plasma flow). To assess the impact of ARC on the PK of antimicrobials, amikacin (7,5 mg/kg BW, Amukin®) was administered after 24 h of fluid therapy. PK modelling was performed with Phoenix® WinNonlin®.ResultsGenerally, an increase in GFR was observed after fluid administration when compared to the GFR values observed without fluid administration. 4 and 2 out of 7 pigs demonstrated ARC after 4 h of a CRI at 3 mL/kg/h and 6 mL/kg/h, respectively. 4 out of 7 pigs displayed ARC after 24 h of a CRI at 3 mL/kg/h and 6 mL/kg/h. Similar results were obtained for amikacin clearance.ConclusionAn important effect of fluid therapy on the development of ARC was observed in juvenile pigs. Further research is necessary to confirm this results in critically ill children.ReferencesDhont E, et al. Augmented renal clearance in pediatric intensive care: are we undertreating our sickest patients? Pediatric Nephrology 2018.Gasthuys E, et al. Postnatal Maturation of the Glomerular Filtration Rate in Conventional Growing Piglets As Potential Juvenile Animal Model for Preclinical Pharmaceutical Research. Frontiers in Pharmacology 2017;8.Disclosure(s)This study was funded by the Special Research Fund of Ghent University (BOF16/DOC/285).
O19 Development of a paediatric brain PBPK model in children with and without meningitis
Authors: Verscheijden LFM , Koenderink JB , Allegaert K , de Wildt SN , Russel FGM 
Published: May 2019

BackgroundSeveral paediatric physiologically-based pharmacokinetic (PBPK) models have been developed that incorporate developmental changes affecting plasma drug concentrations. Disposition into cerebrospinal fluid (CSF) is also age-related and influenced by physiological factors, including CSF production rate, but also by brain diseases, such as meningitis, which are associated with impaired blood-brain barrier integrity. Our aim was to develop a paediatric brain PBPK model to predict CSF drug concentrations in children with and without meningitis.MethodsA paediatric PBPK model was developed incorporating age-appropriate parameters and associated inter-individual variability. The model was validated for paracetamol, ibuprofen, flurbiprofen and naproxen, and for a paediatric meningitis population by estimating meropenem blood-brain barrier penetration using sensitivity analysis. Plasma and CSF drug concentrations derived from literature were used to perform visual predictive checks and to calculate ratios between simulated and observed AUCs in order to evaluate model performance.ResultsSimulated data were comparable to observed over a broad age range (1 day - 15 y postnatal age), for all drugs investigated. The ratios between observed and simulated AUCs were within 2-fold difference both in plasma and in CSF, indicating acceptable model performance. Disposition of meropenem into the brain was slow and CSF concentrations were lower compared to plasma concentrations. In addition, several days were needed to achieve CSF steady-state concentration.ConclusionsOur paediatric brain PBPK model provides a new tool to predict CSF concentrations in children with and without meningitis and can be used as a template model for other drugs acting in the CNS.Disclosure(s)Nothing to disclose
O20 Dose-linearity of the pharmacokinetics of an intravenous [14C]midazolam microdose in children
Authors: van Groen BD , Vaes WHJ , Park BK , Krekels EHJ , van Duijn E , Kõrgvee L-T , Maruszak W , Grynkiewicz G , Garner RC , Knibbe C , Tibboel D , de Wildt SN , Turner MA 
Published: May 2019

BackgroundDrug disposition in children may vary from adults due to age-related variation in drug metabolism, but paediatric pharmacokinetic (PK) studies are challenging. Microdose studies present an innovation to study PK in paediatrics, and can only be used when the PK of a microdose are dose-linear to a therapeutic dose. We aimed to assess dose-linearity of [14C]midazolam (MDZ), a marker for the activity of the developmentally regulated CYP3A enzyme, by comparing the PK of an intravenous (IV) [14C]MDZ microtracer given simultaneously with therapeutic MDZ, with the PK of a single IV [14C]MDZ microdose.MethodsPreterm to 2-year-old infants admitted to the intensive care unit received [14C]MDZ IV either as a microtracer during therapeutic MDZ infusion or as an isolated microdose. Dense blood sampling was done up to 36 hours after dosing. Plasma concentrations of [14C]MDZ and [14C]1-OH-MDZ were determined by accelerator mass spectrometry. A population PK model was developed with NONMEM 7.4 to study whether there was a difference in the PK of the microtracer versus those of a microdose [14C]MDZ.ResultsOf fifteen children (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), nine received a microdose and six a microtracer [14C]MDZ (111 Bq/kg; 37.6 ng/kg). In a two-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the [14C]MDZ microdose or microtracer, suggesting the PK of MDZ to be linear within the range of the therapeutic doses and microdoses.ConclusionOur data supports the dose-linearity of an IV [14C]MDZ microdose in children, thus a [14C]MDZ microdosing approach can be used to study developmental changes in hepatic CYP3A activity.Disclosure(s)This project was funded by the ZonMw ERA-NET PRIOMEDCHILD programme (projectnumber 113205022). * both authors contributed equally
O24 Ivermectin in children: what is the right dose to achieve equivalent exposure coverage in children and adults?
Authors: Brussee JM , Schulz JD , Coulibaly JT , Keiser J , Pfister M 
Published: May 2019

BackgroundThe broad-spectrum antiparasitic drug ivermectin is widely used in children, and its use in children weighing < 15 kg is off-label, as little data is available to inform the use of ivermectin in this young age group. Pediatric doses associated with consistent exposure across age are still unknown. Therefore, we aim to identify a dosing strategy for ivermectin treatment in both pre-school-aged children (2–5 years of age) and school-aged children (6–12 years of age) that achieves equivalent exposure coverage in children and adults.MethodsA population pharmacokinetic model for ivermectin was developed based on data collected in 80 pre-school-aged children (2–5 years), 120 school-aged children (6–12 years),1 and eleven adults,2 receiving an oral dose of 100–600 µg/kg ivermectin. Model-based simulations were performed to optimize pediatric dosing to achieve consistent exposure across various age groups.ResultsClearance per kilogram was higher in children than in adults, with a median (90% confidence interval) of 0.35 (0.12–0.73) L/h/kg in children compared to 0.20 (0.10–0.31) L/h/kg in adults. As a result, ivermectin exposure in children following a 200 µg/kg dose is ∼30% lower than in adults. An increased dose of 250 and 300 µg/kg would be needed in school-aged children (6–12 years) and pre-school-aged children (2–5 years), respectively, to achieve equivalent exposure coverage in children and adults. Alternatively, we propose a height-based dosing schedule with a stepwise increase in number of administered 3-mg-tablets from 1 to 5 for children in sub-Saharan Africa with a height of 75–90 cm, 90–130 cm, 130–150 cm, 150–165 cm, and 165–175 cm.ConclusionWe report the first dosing strategy for the widely-used drug ivermectin that is associated with equivalent exposure coverage in children and adults. Further studies are necessary to establish the safety and efficacy of appropriate doses in the pediatric population.ReferencesWimmersberger D, Coulibaly JT, Schulz JD, Puchkow M, Huwyler J, N´Gbesso Y, et al. Efficacy and Safety of Ivermectin Against Trichuris trichiura in Preschool-aged and School-aged Children: A Randomized Controlled Dose-finding Trial. Clin Infect Dis 2018; 67(8):1247–55.Schulz JD, Neodo A, Coulibaly JT, Keiser J. Development and validation of a LC-MS/MS method for ivermectin quantification in dried blood spots: application to a pharmacokinetic study in Trichuris trichiura-infected adults. Anal. Methods, 2018, 10, 2901–9.Disclosure(s)JMB declares no potential conflicts of interest. JDS declares no potential conflicts of interest. JTC declares no potential conflicts of interest. JK was financially supported by the Bill and Melinda Gates Foundation (OPP1153928) and an ERC grant (CoG 614739 A-HERO), and declares no other potential conflicts of interest. MP has a part-time employment with the consulting company Certara LP (USA), and declares no other potential conflicts of interest.
P04 Non-compartmental analysis of vancomycin pharmacokinetics in critically ill children
Authors: Akunne O , Mugabo P , Argent A 
Published: May 2019

BackgroundVancomycin is often used as the drug of choice in the treatment of bacteria that are methicillin resistant or in patients sensitive to penicillin. This study describes the pharmacokinetics of vancomycin in critically ill children.MethodsChildren aged 1month to 16 years admitted to the paediatric intensive care unit of the Red Cross War Memorial Hospital and on vancomycin treatment for ≥24 hours and ≤72 hours were prospectively recruited. Blood samples were collected around predetermined optimal sampling times. A minimum of three samples per patients was analysed. Non-compartmental analysis was used to determine the volume of distribution (V), clearance (CL), half-life (t1/2), area under the concentration-time curve (AUC), elimination constant (Ke) and Mean residence time (MRT). The minimum concentration (Cmin) and maximum concentration (Cmax) of vancomycin were measured directly as trough and peak plasma concentration respectively. Analysis of data was performed using PKNCA version 0.8.5 in R.ResultsForty-nine serum concentrations from 10 patients were included in the analysis. The ratio of male to female was 1:1. Median age (Range) was 1.6 (0.2–15) years, weight = 10.6 (3.1–31.3) kg, baseline serum creatinine (Scr) = 0.31 (0.15–0.78) mg/dL. Patients received daily vancomycin doses ranging from 56 to 78 mg/kg. Mean PK parameters (range) were as follows: CL = 0.12±0.15 (0.018–0.52) L/h/kg, V =0.68±0.47 (0.15–1.57) L/kg, Ke = 0.147±0.073 (0.07–0.33) h-1, t1/2 =5.54±2.03 (2.11–9.62) h, MRT=8.02±2.92 (3.04–13.88) h, AUC =322.07±245.65 (31.6–850.4) mg/L.h, Cmin =6.21±3.66 (2.0–14.5) mg, Cmax =38.91±31.92 (10.4–97.2) mg. Trough concentration and AUC were not met in >80% and >75% of the patients.ConclusionVariability in vancomycin pharmacokinetics was observed in patients. At current doses, target trough concentrations and AUC were not met.Disclosure(s)Nothing to disclose
P05 Establishing the integrity of the continually paediatric pharmacokinetic bioanalysis for clinical trial within an academia environment using quality assessment process
Authors: Ali M , Tins J , Burckhardt BB 
Published: May 2019

BackgroundEuropean Medicines Agency (EMA) outlines criterion for validation of bioanalytical assay applied under Good Clinical Laboratory Practice (GCLP) within clinical studies. The validation is performed once and does not inevitably ensures comparable reliability over long duration of assay’s applicability. To address this hurdle, the investigator-driven ‘Labelling of Enalapril from Neonates up to Adolescents’ project (LENA) adapted quality system comparable to industry. A comprehensive set of quality measures was applied to ensure reliability of monthly quantified paediatric samples over duration of 31 months.MethodsA 3-step quality approach analysing the calibration standards (CS), quality controls (QCs) and incurred sample reanalysis (ISR) was used to established reliability of unknown samples. Unknown concentrations were reported only if results of known CS (11 levels) and QCs were within the predefined limits. A maximum deviation of ±15% was acceptable at all five QCs level. ISR was conducted for randomly selected paediatric samples to monitor the assay’s performance over time. The acceptable%difference was ±20% for at least 67% of the ISR according to international guidelines. 1,2Results38 analytical runs were conducted for two drugs (enalapril/enalaprilat) from February 2016 to August 2018. Calibration curve evaluation accounted for exclusion of four enalapril and five enalaprilat runs. Additional investigation of QCs resulted in further exclusion of two enalapril and one enalaprilat runs. Within 32 valid runs 820, QCs were measured for enalapril and enalaprilat. 94% enalapril and 89% enalaprilat QCs were within limits (±15%). This set ensured reliable determination of 1262 LENA paediatric study samples. 93 and 104 incurred samples for enalapril and enalaprilat were reanalysed. ISR for enalapril (70%) and enalaprilat (67%) was also within guidelines.1,2ConclusionThe analysis of bioanalytical data ensured the reliability of reported unknown concentrations. It ensured consistent and reliable pharmacokinetic data from first to the last LENA study patient.ReferencesGuideline on bioanalytical method validation. European Medicines Agency, London, UK ( 2011).Guidance for Industry Bioanalytical Method Validation. US Department of Health and Human Services, US FDA, Rockville, MD, USA ( 2018).Disclosure(s)Mohsin Ali, Jutta Tins, Bjoern B Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)
P16 Towards determination of endogenous prorenin in paediatric samples using a hybrid approach – impact of antibody selection for immunocapture
Authors: Burdman I , Burckhardt BB 
Published: May 2019

BackgroundSince sample volume is limited in children, innovative bioanalytical methods and enrichment procedures are highly required. The analysis of endogenous substances by liquid chromatography coupled to mass spectrometry is a highly specific method because of its selectivity and accuracy. However reliable detection of endogenous substances can only be achieved by a hybrid assay approach combining immunocapture and mass spectrometry. Key element of the immunocapture procedure is the selection of the appropriate antibody for capturing the desired antigen. This study is meant to identify the most suitable antibody that facilitates the development of an hybrid assay approach concerning reliable detection of endogenous prorenin in paediatric samples.MethodsDynabeads magnetic beads were coupled to three different antibodies from three different vendors (GeneTex, Molecular Innovations, R&D systems). 500 µL human plasma which was spiked with 20 ng recombinant human prorenin (Cayman chemicals). The immunocapture step was followed by protease digestion and a custom-made µelution solid-phase extraction protocol. The digest was analyzed by Shimadzu Nexera LC-system coupled with Sciex TripleTOF 6600 mass spectrometer.ResultsThe analysis of the captured prorenin was performed by the surrogate peptide approach. In this case the surrogate peptide was identified as unique. The comparison of the three available antibodies showed that one antibody did not ensure reliable binding properties in human matrix. Among the two remaining antibodies only one showed sufficient binding capacities to be applied in small sample volumes commonly available in paediatric samples. Using this hybrid approach enabled the enrichment of the required volume by factor of 20.ConclusionThis study identified the most suitable antibody for the immunocapture procedure of the prorenin hybrid approach. This is now followed by further mass spectrometric method development and validation prior to its application in paediatric samples.Disclosure(s)Declaration of interest: none Ilja Burdman and Bjoern B. Burckhardt declare that there is no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
P23 Evaluation of exposure to vancomycin in neonates with current dosing approaches
Authors: Dao K , Guidi M , Andre P , Giannoni E , Fuchs A , Pfister M , Buclin T , Csajka C 
Published: May 2019

BackgroundSeveral neonatal dosing recommendations for vancomycin are found in the literature, variably based on age, renal function and body weight. Still there is no consensus regarding optimal initial dosing in term or preterm neonates. Our objective was to evaluate and compare how current dosing approaches perform with respect to target plasma concentration attainment, using a comprehensive population PK model of vancomycin developed in a large cohort of neonates.MethodsA single-compartment, linear elimination population pharmacokinetic model incorporating postmenstrual age, kidney function and body weight as covariates was elaborated using NONMEM®, based on 1848 vancomycin concentration values measured in 405 neonates during routine TDM. The model was then used to simulate the distribution of vancomycin concentrations resulting from 20 dosing guidelines identified in the literature. Proportions of patients within and above target exposure were used as a performance measure of each dosing regimen, defining target as AUC24/MIC ratio of 400–700 h and trough concentration of 10–20 mg/L, both on days 1 and 7 of treatment.ResultsOnly 2 out of 20 current dosing recommendations (Neonatal Formulary 7 and Neofax® meningitis regimens) ensured target attainment in about 60% of neonates on both days 1 and 7. Most other guidelines produced below-target exposure in a large fraction of patients (22–97%), except two that frequently produced overexposure (55–66%).ConclusionA majority of currently used vancomycin dosing regimens proposed in the literature failed to ensure target attainment in at least 60% of neonates. It is important that concentration exposure associated with best chances of therapeutic success is promptly reached, in particular in neonatal units having a high prevalence of coagulase negative Staphylococci. We recommend electing an effective dosage regimen, with a loading dose, to ensure early target attainment in a majority of patients. Subsequent therapeutic concentration monitoring remains warranted to further individualize vancomycin dosage and optimize exposure in all patients.Disclosure(s)Nothing to disclose
P29 A smartphone application to monitor nausea in pediatric cancer patients during chemotherapy
Authors: Eliasen A , Abildtoft MK , Krogh NS , Brok JS , Mathiasen R , Schmiegelow K , Dalhoff KP 
Published: May 2019

BackgroundNausea is a common and distressing side effect for children in chemotherapy. Antiemetic recommendations are based on limited literature and prospective evaluation of antiemetic efficacy is required. Smartphone applications (apps) may collect patient-reported outcomes with precision and effectiveness1. We developed a smartphone app to track nausea in pediatric cancer patients during chemotherapy.MethodsMedical researchers, pediatric oncologists and software engineers worked synergistically in the development. We translated the validated Pediatric Nausea Assessment Tool to score nausea severity2. We conducted three rounds of patient-feedback and modification.ResultsThe app has a definition module where the child centers the attention to the concept of nausea. The child can then express nausea severity with four faces and the child’s own definition of nausea is incorporated in the question2. The app includes a notification system to ensure high response rates. All participants felt that the app was user-friendly, intuitive and that time spent was acceptable.ConclusionThe app is a user-friendly tool to assess nausea in pediatric cancer patients that can ease future pediatric antiemetic trials.ReferencesStone AA, Shiffman S, Schwartz JE, et al. Patient compliance with paper and electronic diaries. Control Clin Trials 2003 Apr;24(2):182–99.Dupuis LL, Taddio A, Kerr EN, et al. Development and validation of the pediatric nausea assessment tool for use in children receiving antineoplastic agents. Pharmacotherapy 2006;26:1221–31.Disclosure(s)Nothing to disclose
P30 Limited sampling strategies to predict valganciclovir exposure in kidney transplanted children
Authors: Benyoub N , Facchin A , Magreault S , Jacqz-Aigrain E , Elie V 
Published: May 2019

BackgroundGanciclovir and its pro-drug, valganciclovir, are anti-viral drugs used in cytomegalovirus infections treatment in kidney transplanted children. Both present a high pharmacokinetic variability requiring dosage individualization and Therapeutic Drug Monitoring to ensure optimal therapeutic exposure. This retrospective monocentric study aimed to develop a Limited Sampling Strategy (LSS) predicting Area Under the Curve (AUC0-24h) reducing the number of blood samples to improve and facilitate kidney transplanted children medical care.MethodsPediatric kidney transplanted children treated with valganciclovir were included. Rich pharmacokinetic data from ganciclovir plasmatic dosages (sampling times at 0h, 1h, 2h, 4h, 8h, 12 h and 24 h) were collected between February 2005 and November 2018. Ganciclovir exposures at steady-state (AUC0-24h) were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC0-24h. The overall patients population was divided into two groups for model development and validation purposes.Results129 patients were included: 46 girls and 83 boys, mean age at transplantation was 11.3years ± 5.1. Multilinear regression models were developed on 85 pharmacokinetic profiles (85 patients, mean AUC0-24h=64µg.h/mL ± 27, creatinine clearance=72.4 mL/min per 1.73 m2) and validated on an independent group of 73 pharmacokinetic profiles (44 patients). Regressions based on samples collected at 0, 2, 4 h (R=0.946) or 0, 2, 8 h (R=0.968) presented the best AUC0-24h predictive performances (RMSE=7.5 and 6.6, MAE=5.7 and 4.8 respectively) with an average difference between reference and predicted AUC0-24h of -0.52 and 0.67µg.h/mL respectively.ConclusionsTo date, this is the largest cohort of valganciclovir treated pediatric transplanted children used to develop a LSS. This LSS allows to accurately predict ganciclovir AUC0-24h in pediatric transplanted patients using 3 pharmacokinetic blood samples at 0h, 2h, and 4 h post-dose. Beside other Bayesian estimators developed in the literature, this multilinear regression can be easily implemented into daily practice facilitating patients care.Disclosure(s)Nothing to disclose