bluuebunny/crossref_metadata_2025_split huggingface dataset:
P70 Identifying and managing problematic polypharmacy in children and young people?
Authors: Moss J , Austin R , Hawcutt D 
Published: May 2019

BackgroundPolypharmacy may be necessary in a patient with complex disease or multiple illnesses. Problematic polypharmacy (PP) is defined as the prescribing of multiple medications inappropriately, or where the intended benefit of the medication is not realised. Identification and management of PP already occurs in adult medicine, with evidence based guidelines and deprescribing tools available. This work aims to establish the extent of polypharmacy affecting children at our centre, and the existence of evidence based de-prescribing guidelines to manage potential PP.MethodsAudit of children and young people prescribed medications at a secondary and tertiary children’s hospital, January - December 2017. A systematic review looking for evidence of such a deprescribing tool or guideline was registered with PROSPERO, and undertaken. Inclusion criteria specified the need for a guideline or deprescribing tool in children from birth to < 18yrs of age. Two independent reviewers performed the review with a third reviewer resolving any discrepancies.ResultsWithin a secondary and tertiary care children’s hospital, 668 children were identified as receiving >10 drugs concurrently, while 30 were receiving >20 drugs at one time.The systematic review identified 563 papers initially, with 482 remaining once duplicates were removed. After application of inclusion and exclusion criteria, two studies were included, POPI (Prot-Labarthe et al, 2014) and PIPc (Barry et al, 2016). These papers discuss systems to identify inappropriate prescriptions. No evidence based guidelines related to the management of potential PP in children were identified.ConclusionThere are children receiving a large number of medicines concurrently, putting them at risk of PP. No specific deprescribing guideline or tools to guide management were identified. Paediatric clinical pharmacology is well placed to create and implement such guidelines.Disclosure(s)Nothing to disclose
P73 Paediatric population pharmacokinetic modeling for gentamicin – is the current dose recommendation justified?
Authors: Paioni P , Berger C , Krämer SD 
Published: May 2019

BackgroundMonitoring of gentamicin serum trough level (Cmin) is standard practice in children to prevent toxicity by accumulation1. Cmin < 2 mg/L are recommended. Peak serum concentration (Cmax) is not routinely measured although Cmax between 10 and 12 mg/L have been recommended balancing efficacy and toxicity2,3. We aimed to develop a population pharmacokinetic (PK) model for gentamicin in children to optimise current dosing regimens.MethodsAll patients receiving once daily intravenous gentamicin (5 mg/kg in children < 7 days and 7.5 mg/kg in children >7 days of age) at the University Children’s Hospital Zurich between 10/2017 and 01/2019 were eligible for this study. Children with cystic fibrosis and renal replacement procedures were excluded. Routine Cmin were measured in all patients before administration of the second or third dose. Additional gentamicin serum levels were measured 30 min (C30) and 4 h after the second dose in patients giving written informed consent. Data were analysed by non-linear mixed-effects modeling.Results165 patients (median age 34 days; IQR 15–56 days) were included in the study. A total number of 103 C30 and 166 Cmin measurements were available, respectively. C30 (mean 19.7 mg/L, SD ±6.1 mg/L) was >12 mg/L in 94/103 (91%) and Cmin >2 mg/mL in 3/166 (1.8%) measurements. The PK model successfully predicted most C30 >12 mg/L but performed poorly at the through levels.ConclusionsOur current gentamicin dosing regimen rarely leads to accumulation but most Cmax are above optimal range. The latter was successfully modelled. Although no evidence for a Cmax upper limit exists, toxicity has been associated with high drug exposure3. This calls for an adjustment of our dosing regimen using our PK model based on body height or weight in order to lower exposure. Further studies investigating the relationship between Cmax levels and clinical outcome and additional data for PK model testing are needed for validation.ReferencesRitz N, Bielicki J, Pfister M, van den Anker J. Therapeutic Drug Monitoring for Anti-infective Agents in Pediatrics: The Way Forward. Pediatr Infect Dis J. 2016;35(5):570–572.Chattopadhyay B. Newborns and gentamicin-how much and how often? J Antimicrob Chemother. 2002;49(1):13–16.Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet. 2009;48(2):71–88.Disclosure(s)Nothing to disclose
P83 CYP2D6 phenotyping in children treated with tramadol at the Emergency Department
Authors: Rodieux F , Storelli F , Manzano S , Gervaix A , Posfay-Barbe K , Samer C , Daali Y , Desmeules J 
Published: May 2019

BackgroundPain management is essential and opioids side effects are of major concern. Tramadol safety and efficacy is influenced by CYP2D6 activity. Phenotyping measurement is available to assess CYP2D6 activity and allow a safe precision medicine approach.4 However need for administration of a probe drug and invasive sampling limit its use. Our objective is to evaluate direct measurement of M1/tramadol ratio and pupillometry as phenotyping methods to identify CYP2D6 ultrarapid (UM) and poor (PM) metabolizers in children treated with tramadol.1-6MethodsWe plan to include 53 children receiving their 1st dose of tramadol at the Emergency Department (ED) of the Geneva Children’s Hospital. Children with concomitant inhibitors/inducers of CYP2D6 and CYP3A or drug with an impact on pupil size are exclude. Standard CYP2D6 phenotyping is performed by measuring blood dextrorphan/dextromethorphan (DOR/DEM) using dried blood spots (DBS) at least 90min after dextromethorphan and tramadol administration. Tramadol and its active metabolite, M1, concentrations are also performed using DBS at the same time. Pupillometry is performed at time of tramadol administration and 1 to twice per hour, during the stay in the ED.ResultsWe included 26 children, median age 10.7 years, of which 2 are UM (8%) and 3 PM (12%), corresponding to what is expected in the Caucasian population. We found a positive correlation between DOR/MED and M1/tramadol ratio (R2= 0.389, p = 0.0006). Pupillometry analyses are in progress. Tramadol 2 mg/kg orally was well tolerated in all children, including UM and PM.ConclusionOur study shows that it is possible to determine CYP2D6 activity in order to provide safe and effective tramadol prescription in children in a less invasive manner than by administering a probe drug, by directly determining the metabolic ratio between tramadol and its metabolite, M1 in children treated with tramadolReferencesFliegert, F., B. Kurth, and K. Gohler, The effects of tramadol on static and dynamic pupillometry in healthy subjects-the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status Eur J Clin Pharmacol, 2005. 61(4): p. 257–66.Slanar, O., et al., CYP2D6 polymorphism, tramadol pharmacokinetics and pupillary response Eur J Clin Pharmacol, 2006. 62(1): p. 75–6; author reply 77–8.Slanar, O., et al., Miotic action of tramadol is determined by CYP2D6 genotype Physiol Res, 2007. 56(1): p. 129–36.Kirchheiner, J., et al., Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol J Clin Psychopharmacol, 2008. 28(1): p. 78–83.Matouskova, O., et al., Pupillometry in healthy volunteers as a biomarker of tramadol efficacy J Clin Pharm Ther, 2011. 36(4): p. 513–7.Connelly, M.A., et al., Pupillometry: a non-invasive technique for pain assessment in paediatric patients Arch Dis Child, 2014. 99(12): p. 1125–31.Disclosure(s)Nothing to disclose
P85 Prediction of raltegravir plasma concentration in HIV paediatric patients using physiologically-based pharmacokinetic model
Authors: Salem F , Abduljalil K , Johnson T 
Published: May 2019

BackgroundRaltegravir is a drug used to treat patients with HIV infection. Understanding the disposition kinetics including the ontogeny of the major metabolic enzyme (UGT1A1) is important in prediction of raltaeravir pharmacokinetics in paediatric patients.MethodsSim-Raltegravir compound file in Simcyp simulator version 18 was used to predict pharmacokinetics in paediatric subjects aged 4 weeks to 6 months, 0.5 to 2, 2 to 6 and 6 to 12 years. Details of trial design were matched as closely as possible with a clinical study.1 Rate of absorption and variability in first order absorption model within Simcyp were set to the reported values. Predicted plasma concentration time profiles with 5th and 95th percentile were compared with observations.ResultsThe predicted vs. observed geometric mean area under plasma concentration-time profile of raltegravir was 18.4 vs. 22.3 µM.h in subjects 4 weeks to 6 months and 16.5 vs. 19.8 µM.h in those 0.5 to 2 years old. In 2 to 6 and 6 to 12 year olds around 80% and 85% of observed data were within 5th and 95th percentile of the predictions.ConclusionThe results show that the UGT1A1 ontogeny profile in the Simcyp version 18 adequately addressed age-related differences in pharmacokinetics of raltegravir.ReferenceRizk, M., et al, J Clin Pharmacol 2015; 55(7):748–56Disclosure(s)Nothing to disclose
O14 Paternal acitretin exposure and pregnancy risks
Authors: Nørgaard M , Andersen JT 
Published: May 2019

BackgroundIn the literature it is well known that acitretin is highly teratogen when used in pregnant women. Therefore, several restrictions to all fertile women prior, during and up to three years after ended treatment are recommended. However, as for paternal acitretin exposure data is very limited leading to worries and anxiety among couples planning or already pregnant.MethodsWe conducted a nationwide cohort study during the period between 1996–2016 investigating paternal acitretin exposure and the risk of spontaneous abortions and the association to major malformation. Data were obtained from the Medical Birth Registry and the National Hospital Registry. All fathers exposed to acitretin were identified by the Danish National Prescription Registry.ResultsWe identified in total 1.477.252 registered pregnancies with known father identity. Of these 244 pregnancies and 205 children were exposed to paternal acitretin treatment between one year prior to conception to the end of first trimester. The adjusted hazard risk (HR) of spontaneous abortion was 0.71 (95% CI: 0.43–1.17). When analysing exposure three months prior to conception and during first trimester only, the adjusted HR was 0.76 (95% CI:0.38–1.51) and 1.06 (95% CI:0.55–2.04), respectively. As for the association between major malformation and paternal acitretin exposure between one year prior to conception to the end of first trimester the adjusted odds ratio (OR) was 1.15 (95% CI: 0.57–2.34). When stratifying for the period of acitretin exposure the same insignificant trend was detected. In addition, both spontaneous abortions and major malformation were independent of dosage.ConclusionWe found no increased risk of spontaneous abortions or major malformation in pregnancies exposed to paternal acitretin one year before to three months after conception. This was persistent when sub-analysing exposure period and dosage. These data are an important contribute to the sparse evidence suggesting that paternal acitretin exposure during fertility is safe.Disclosure(s)Nothing to disclose
P118 ‘Medicines for Children’ project: putting families and carers in the centre
Authors: Zolotas E , Sammons H , Tuthill D , Barker C , Tomlin S , Partridge L , Rossiter A , Osmond V , Barham H , Fox A ,   Medicines For Children Project Board
Published: May 2019

Background‘Medicines for Children’ (MfC) is a joint initiative between the children´s charity WellChild, the Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group. The project aim is to provide parents and carers with reliable, accurate and accessible information about their child’s medicines.MethodsIn 2006, 600 parents and carers were surveyed in order to understand what information was needed. Paediatricians, pharmacists and a medical editor then liaised with WellChild to develop a leaflet template and wrote a set of pilot leaflets. The leaflet production was subsequently standardised. An eight-step process is followed including consultation with health professionals, families and carers. The leaflet library and a series of information videos has grown, with the assistance of a dedicated group of volunteer authors. Published leaflets are reviewed every three years. Access to information is free of charge. The project is funded by the 3 partner groups and not by pharmaceutical companies.ResultsMfC hosts over 230 leaflets and videos. The MfC website1 was launched in 2009. It was subsequently reviewed by parents and carers and re-developed in 2011 and 2015. MfC has users accessing the site from every country in the world. The information leaflets have been viewed over 3 million times in 2018, up from 7,200 in 2009. In 2014, an independent audit of MfC found that over 90% of the parents surveyed thought that the leaflets had an appropriate layout and conveyed the information in lay terminology. Since 2011, MfC information leaflets have been certified by National Health Service Information Standard as providing high quality health information for the public.ConclusionMfC is a successful and acclaimed project which provides high quality, reliable and accurate medicines information worldwide for more than a decade.Referencehttps://www.medicinesforchildren.org.uk/.Disclosure(s)Nothing to disclose.
O02 Developmental pharmacogenetics of SLCO2B1 on montelukast pharmacokinetics in chinese children
Authors: Li Q , Wang K , Shi H-Y , Y-E Wu , Zhou Y , Kan M , Zheng Y , Hao G-X , Yang X-M , Yang Y-L , L-Q Su , Wang X-L , Jacqz-Aigrain E , Zhao W 
Published: May 2019

BackgroundMontelukast, a potent orally selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma.Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed significant inter-individual variability on pharmacokinetics.None of pharmacokinetic study has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of this study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1on Montelukast pharmacokinetics in Chinese paediatric patients.MethodsAfter oral administration with montelukast, opportunistic samples were collected from asthma children and plasma concentrations were determined by high performance liquid chromatography coupled with fluorescence detector (HPLC-FLD) method. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped.ResultsFifty patients (age range 0.7–10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in subjects with SLCO2B1 c.935GA and c.935AAgenotype compared withSLCO2B1 c.935GGsubjects (0.94±0.26 versus 0.77±0.21, p=0.020). Weight was also found to be significantly corrected with montelukast clearance (p 0.0001).ConclusionsThe developmental pharmacogenetics of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype showed independently significant impacts on theclearanceofmontelukast.Disclosure(s)Nothing to disclose.
O21 Progress towards Therapeutic Drug Monitoring via breath analysis
Authors: Singh KD , Ziesenitz V , Usemann J , Van Den Anker J , Frey U , von der Weid N , Datta A , Sinues P 
Published: May 2019

BackgroundTherapeutic Drug Monitoring (TDM) is essential aspect for the clinical management of patients. However, despite the clear advantages of TDM, it faces several challenges to being more widely used in the clinic. Specially challenging is the case of TDM in children, as they experience rapid physiologic developments, leading to great pharmacokinetic and pharmacodynamic variability. Breath analysis provides a patient-friendly approach to support TDM. To explore this possibility, we are currently running a pilot study, whereby we analyze the exhaled breath of pediatric patients receiving anti-seizure or chemotherapy drugs requiring TDM.MethodsWe analyzed by secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) exhaled breath of pediatric patients under therapy for Valproic acid (VPA; n = 27), Lamotrigine (n = 19), Levetiracetam (n = 15), Oxcarbazepine (n = 11) and Methotrexate (n = 4). Systemic blood concentrations were measured simultaneously to the breath test. In the case of VPA, we constructed a regression model to predict systemic blood concentrations based on the signal intensity of breath mass spectral features. For the rest of the drugs listed, due to its current limited size, we conducted preliminary data visualization approaches.ResultsWe found that exhaled metabolites of VPA allow to predict free VPA blood concentrations with a root-mean-square error of 1.5 mg/L for concentrations in the range 0–12 mg/L. This prediction is accomplished within 20 minutes, comprising the breath test and data analysis. For Levetiracetam, Lamotrigine and Oxcarbazepine the data analysis is still ongoing. For MTX we found breath metabolites clearly altered as a result of the drug administration. However, a great inter-individual variability was also observed.ConclusionWe conclude that breath analysis may support current TDM approaches. This will lead to new opportunities to guide the dose of drugs with a high level of accuracy, in real-time and non-invasively.Disclosure(s)PS gratefully acknowledges the financial support of the Fondation Botnar (Switzerland) and the Swiss National Science Foundation (320030_173168 and PCEGP3_181300). PS is part of the board of directors of Deep Breath Initiative AG. JU was supported by research fellowship of the University Children’s Hospital Basel. VS and JVDA were supported by the Eckenstein-Geigy Foundation. *AD and PS: shared senior authorship
O22 3D printed polyethylene oxide oral doses with innovative ‘radiator-like’ design: impact of molecular weight on mechanical and rheological properties and drug release
Authors: Peak M , Baj K , Isreb A , Wojsz M , Mohammad I , Albed Alhnan M 
Published: May 2019

BackgroundDespite regulatory advances, lack of age-appropriate formulations (AAFs) remains a challenge in paediatric practice. 3D-printing of oral dosage forms (ODFs) offers potential for AAFs for children. Optimising drug release from 3D-printed ODFs is an important technological step. Despite the abundant use of polyethylene oxides (PEOs) and their extensive use as an excipient, there have been no previous reports of applying this thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. We assessed the impact of polymer molecular weight (MW) on the mechanical properties of the resultant filaments and their rheological properties. In the FDM 3D printing process, we also tested the effect of an innovative radiator-like design of the ODF on the acceleration of drug release patterns.MethodsBlends of PEO (MW: 100K, 200K, 300K, 600K or 900K) with PEG 6K (plasticiser) and a model drug (theophylline) were prepared by hot-melt extrusion. The resultant filaments were used as a feed for a FDM 3D printer to fabricate innovative designs of ODFs in a radiator-like geometry with inter-connected paralleled plates and inter-plate spacing of either 0.5mm, 1mm, 1.5mm or 2mm.ResultsVarying blends of PEO and PEG allowed formation of mechanically resistant filaments (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with 100K, 200K, 300K, 600K or 900K, respectively). Filaments of PEO at a MW of 200K-600K were compatible with FDM 3D printing. Further increase in PEO MW resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing. A minimum spacing (1 mm) between parallel plates of the radiator-like design was essential to boost drug release from the structure.ConclusionThese findings are essential in the development of next-generation personalised drug delivery doses using specialised polymer/polymer blends purposely optimised for FDM 3D printing.Disclosure(s)Nothing to disclose
O33 Towards personalised weaning of sedatives and analgesics using mechanism-based modelling of iatrogenic withdrawal in critically ill children
Authors: Goulooze S , Krekels E , van Dijk M , Hankemeier T , Tibboel D , Ista E , Knibbe C 
Published: May 2019

BackgroundProlonged treatment with analgesics and sedatives can result in iatrogenic withdrawal syndrome (IWS) in children being weaned from these drugs.1Personalized weaning strategies might lower the incidence of IWS, but this requires a quantitative understanding of withdrawal over time in individual patients.MethodsData from 81 children (aged 1 month to 17 years) collected during an observational clinical study on IWS2 were used, including a total of 1782 withdrawal assessments performed by PICU nurses, on a numerical rating scale (NRSwithdrawal) from 0 (no withdrawal) to 10 (worst withdrawal possible). Population pharmacokinetic models from literature were used to generate concentration-time profiles in each patient of all key analgesics and sedatives: morphine, fentanyl, methadone, midazolam, lorazepam, propofol, esketamine and clonidine. A mechanism-based withdrawal model was developed using NONMEM 7.3 to quantify IWS over time. The final model was used to perform simulations in which different weaning strategies were compared.ResultsA novel mechanism-based withdrawal model structure was developed with a hypothetical compartment, which equilibrates with the central pharmacokinetic compartment, and which characterizes the development and disappearance of drug dependence over time. With this model and available data, withdrawal dynamics could be established with statistical significance for fentanyl (p< 10-6), morphine (p=0.043) and esketamine (p=0.002), and not for any of the other drugs. Compared with fentanyl, development and disappearance of esketamine and morphine dependence is slower.ConclusionsGiven the patient‘s use of fentanyl, morphine and esketamine, the developed model can dynamically predict IWS from these substances under different weaning strategies. The results show that the optimal strategy for weaning of drug dependent children depends on both the type of drug and the drug levels prior to weaning. In this study, there was insufficient information to characterise midazolam withdrawal dynamics, potentially because of slow midazolam weaning with insufficiently high NRSwithdrawal scores.ReferencesBest KM, Boullata JI, Curley MAQ. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: A Systematic Review and Conceptual Model. Pediatr Crit Care Med ( 2015) 16(2): 175–183.Ista E, de Hoog M, Tibboel D, Duivenvoorden HJ, van Dijk M. Psychometric evaluation of the sophia observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med ( 2013).14(8): 761–769.Disclosure(s)Nothing to disclose