bluuebunny/crossref_metadata_2025_split huggingface dataset:
P87 The Swiss Association of Perinatal Pharmacology, SAPP: goals
Authors: Schenkel L , von Mandach U ,   The Editorial Board of the SAPP
Published: May 2019

BackgroundThe medicine of pregnant women practices to a targeted personalized approach, tailored to the specific characteristics and needs the implications of interdisciplinary work between healthcare stakeholders. Perinatal pharmacology comprises the impact of substances (drugs, medications and others) in pregnant women, nursing mothers, the unborn child, the premature, the newborn baby and the breastfed baby. Most of the drugs are off-label used. In this field grand challenge for Frontiers in Medicine emphasizes the importance of translational medicine.AimThe primary goal of SAPP has always been and remains the same: it is the link between medicine and pharmacy, between practice, clinic, research and health authorities, in order to increase the safety of medicines in the population of pregnant and breastfeeding women and their newborns.1MethodsOn December 6, 2007, an interdisciplinary team of 8 physicians and pharmacists founded the Swiss Association of Perinatal Pharmacology, SAPP. It collects and promotes new findings in the field of perinatal pharmacology.ResultsSpecialists from all areas of perinatal pharmacology work together in a scientific committee to develop and update evidence-based principles for work in everyday clinical practice (hospitals, doctor´s surgeries, pharmacies). Today, around 200 members benefit from this, who can orient themselves in regular further training courses and basic documents (monographs of active substances, therapy recommendations based on original literature). The SAPP thus closes the gap resulting from the predominant off-label use and the resulting lack of information on drugs in this population.ConclusionThe primary objective of SAPP has been achieved - it provides guidance for the practioners in the broad field of perinatal pharmacology and bridges the gap caused by the lack of drug approvals in this population. Long-term survival will be ensured by measures anchored in law.Referencewww.sappinfo.chDisclosure(s)Nothing to disclose
P89 Emicizumab development in paediatric patients with congenital hemophilia A and inhibitors against factor VIII
Authors: Schmitt C , Yoneyama K , Chang T , Retout S , Grimm H -P , Levy GG 
Published: May 2019

BackgroundEmicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX (FIXa) and FX, restoring missing FVIIIa function in patients with hemophilia A (PwHA). It has been recently approved for routine prophylaxis of bleeding episodes in PwHA with FVIII inhibitors in all age groups. We herein describe the paediatric development of emicizumab with a focus on dose selection, study design and extrapolation of efficacy.MethodsThe dosing regimen for the HAVEN 1 study (adolescents/adults) was selected based on the exposure-response (annualized bleeding rate [ABR]) relationship derived from a phase I/II study in adolescent/adult PwHA. Pharmacokinetic (PK) simulations, with or without maturation of clearance (CL MAT), were performed to guide selection of the dosing regimen for the HAVEN 2 study (paediatrics) aiming to achieve the same target exposure as in HAVEN 1. HAVEN 2 employed a flexible design with possibility for individual- and population-level dose up-titration. Additional PK modeling and simulations together with exposure-response analyses were used to support full extrapolation of efficacy in any age category where no data was available.Results1.5 mg/kg/week in HAVEN 1 provided mean trough concentrations of ∼50 µg/mL and was associated with a 87% reduction in ABR. Doses of ≥ 1.5 (with CL MAT) and ≥ 2.25 mg/kg/week (without CL MAT) were predicted to achieve this target exposure in children. HAVEN 2 began by investigating the same dose as HAVEN 1. Similar trough concentrations of ∼ 50 µg/mL were achieved in children and were associated with low ABR. No patients < 1 year were enrolled in HAVEN 2. PK simulations and pharmacological rationale suggested that a different dose for these patients was not warranted.ConclusionsEfficacy of emicizumab in adolescents/adults was demonstrated in HAVEN 1, partially extrapolated to HAVEN 2 participants 1–11 year of age, and fully extrapolated in patients < 1 year.Disclosure(s)Authors are Roche/Genentech employees
P91 Real-time breath analysis of antiepileptic drugs
Authors: Singh KD , Ziesenitz V , Usemann J , Frey U , van den Anker J , Datta A , Sinues P 
Published: May 2019

BackgroundIn the field of medicine, serum concentrations of drugs with a narrow therapeutic window, used to treat seizures, are measured to assure the most efficacious and safe way of treating every individual patient. This form of personalised medicine is called therapeutic drug monitoring (TDM). We have explored the possibility to measure and monitor drugs in exhaled breath (EB), to perform completely painless and non-invasive TDM for a future clinical application especially in pediatric patients.MethodsWe employed secondary electrospray ionisation in combination with high resolution mass spectrometry to obtain highly resolved EB mass spectra. We then statistically compared these EB mass spectra between patients taking antiepileptic drugs against controls (no drugs), to find potential EB-based bio-markers for drugs. Suspected drug metabolites detected in breath will be compared with systemic blood concentrations. We will screen a total of 15 drugs requiring TDM.ResultsSo far we have successfully measured EB mass spectra of patients undergoing treatment with Valproic acid (VPA, n = 27), Lamotrigine (n = 19), Levetiracetam (n = 15) and Oxcarbazepine (n = 11). Exploratory data analyses are still ongoing for these drugs. However, for VPA we have identified few candidate ions which enables us to predict free VPA blood concentrations (RMSE 1.5 mg/L). Additionally, we have positively identify two molecules involved in free VPA prediction, based on LC-MS/MS of the exhaled breath condensate. In the near future we will continue to perform data analyses and LC-MS/MS on ions of interest to confirm their identity.ConclusionsThis work is a part of an ongoing study and it is too early to come up with a definite conclusion. However, we observed several differentially abundant ions between controls and epileptic patients for various drugs, but the identity and clinical significance of these ions is yet to be determined.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. VZ and JV are supported by the Eckenstein-Geigy Foundation. *AD and PS: shared senior authorship.
P92 Metabolomics in children with heart failure using ACE-inhibitors, an exciting opportunity?
Authors: Smeets N , Dalinghaus M , de Wildt S 
Published: May 2019

IntroductionACE inhibitors (ACEi) have a prominent place in the treatment of heart failure in children. However, there is a significant interpatient variability in efficacy and safety in those children that is not completely understood. Metabolomics provides an interesting innovative approach to better understand underlying mechanisms for variation in disease and response to therapy. With this review, we aim to provide an overview of metabolomics in the field of heart failure therapy with or without ACEi in both adults and children and try to identify gaps in this field.MethodsThe PubMed database was systematically searched using several search strategies. Articles were labelled as relevant when they included information on either metabolomics of adult patients with heart failure and/or ACEi-therapy or in children. This yielded 42 relevant articlesResults24 articles were found describing metabolomics in adults with heart failure, either with or without ACEi-therapy. In addition, several metabolites were identified in adults correlating with either ACEi-efficacy or safety. No metabolomics articles were found in children with heart failure or in children on ACEi-therapy. Several papers (18) were found on metabolomics in children for other diseases and/or treatments.ConclusionMetabolomics in adult heart failure patients has helped to unravel part of observed disease and therapy variability, and appears helpful in identifying patients at risk for therapy failure as well as detecting novel targets for heart failure therapy. In children, a significant information gap exists. This provides exciting opportunities for personalized treatment of heart failure.Disclosure(s)This work was partially supported by LENA, a Collaborative Project funded by the European Union under the 7th Framework Programme under grant agreement n° 602295.
P93 Semi-mechanistic modelling of hydrocortisone pharmacokinetics in paediatric patients with adrenal insufficiency
Authors: Stachanow V , Melin J , Michelet R , Blankenstein O , Neumann U , Ross R , Whitaker M , Huisinga W , Kloft C 
Published: May 2019

BackgroundPatients with congenital adrenal hyperplasia (CAH) have low to no biosynthesis of cortisol and require lifelong cortisol replacement. Optimisation of hydrocortisone (HC, synthetic cortisol) therapy in this population is important, since too low or high cortisol concentrations increase the risk of adrenal crisis or Cushing’s syndrome1. HC has nonlinear pharmacokinetics (PK) caused by saturable binding to corticosteroid binding globulin (CBG)2. The objective of this analysis was to extend an established paediatric HC PK-model3 with dried blood spot (DBS) data in order to further characterise the binding behaviour of HC in children.MethodsA semi-mechanistic adult PK model for a novel HC formulation4 has previously been reduced to a paediatric model using sparse plasma samples from a phase III study in 24 patients with adrenal insufficiency5. Plasma and DBS concentrations of cortisol were collected and additional DBS HC concentrations were obtained from a follow-up study. The relation between plasma and DBS samples was characterised by a graphical evaluation, after which nonlinear mixed-effects modelling was applied using NONMEM 7.4.ResultsPlasma concentrations of cortisol were substantially higher than the corresponding DBS concentrations. The plasma/DBS ratio ranged between 2 to 8 within and between children, while the relation between the cortisol DBS concentrations and cortisol plasma concentrations showed nonlinear behaviour mirroring the nonlinear binding kinetics to CBG.ConclusionsOur graphical analysis identified substantial differences and high inter- and intraindividual variabilities between plasma and DBS samples. A nonlinear mixed-effects model is being set up to quantify these findings and allow for further prediction of HC exposure. Afterwards, effect biomarkers can be included in order to evaluate cortisol replacement therapy and to optimise the HC treatment in paediatric patients.ReferencesSpeiser PW, et al. J Clin Endocrinol Metab 2010;95(9):4133–4160.Lentjes EG, WM, et al:J Clin Endocrinol Metab. 1999;84(2):682–687.Melin J:Dissertation 2017.Melin J, et al:Clin Pharmacokinet. 2018;57(4):515–527.Neumann U. et al:Clin Endocrinol. 2018;88(1):21–29.Disclosure(s)Nothing to disclose
P101 Extending the Dutch Paediatric Formulary across Europe: successful development of country specific, parallel, paediatric drug formularies
Authors: Van der Zanden T , Neubert A , Zahn J , Wimmer S , de Hoop M , Rosness T , Kjeldby-Høie C , Teigen A , Male C , Rauch E , Lagler F , Rascher W , de Wildt S 
Published: May 2019

BackgroundsAs many drugs in paediatrics are used of off-label, prescribers across Europe face a lack of evidence-based dosing guidelines. The Dutch Paediatric Formulary (DPF) was developed to provide dosing guidelines based on best available evidence from registration data, investigator-initiated research, clinical experience and consensus (1). The DPF has recently joined forces with Germany, Norway and Austria aiming to develop multi-language, parallel, paediatric drug formularies based on the DPF.MethodsThe DPF database and ICT framework were extended to a duplicate database for Germany. The dosing guidelines were translated to German and reviewed for fit with German practice. Relevant drugs and dosing recommendations were selected and country-specific information was added to address country-specific needs. Work-sharing on content development was studied in a small pilot.ResultsThe German Pediatric Formulary (www.kinderformularium.de) was launched on 1 October 2018 within a German paediatric medication safety project (KiDSafe). At that time 119 of 769 drugs were reviewed and published in the German formulary.The dosing recommendations of the DPF show a good fit with German practice; i.e. adaptations were needed in less than 10% of the cases caused by differences in licensing status, national guidelines or availability of formulations. There were no differences in interpretation of evidence. Nine drugs - highly relevant for German practice, but not listed in the DPF, were added to the German formulary based on SmPC. The content work sharing was piloted by the development of a new monograph and the periodic revision of a monograph complying to the Dutch standard operating procedure by Germany. This pilot has shown the feasibility of work-sharing in developing and updating drug monographs.ConclusionThe Dutch framework has successfully been extended to the German situation. Work-sharing on the development of dosing recommendations is feasible. Similar extension to Norwegian and Austrian nation-wide formularies has started.Referencesvan der Zanden T, De Wildt S, Liem T, Offringa M, de Hoog M. Developing a pediatric formulary for the netherlands. Arch Dis Child 2017;Apr;102(4):357–61.Disclosure(s)Tjitske van der Zanden is managing director of the Dutch Paediatric Pharmacotherapy Expertise Network; Saskia de Wildt is medical director of Dutch Paediatric Pharmacotherapy Expertise Network. The other authors have no financial disclosures relevant to this article.
P111 Developmental pharmacogenetics of CYP2D6 in Chinese children: loratadine as a probe drug
Authors: Li Q , Y-E Wu , Wang K , Shi H-Y , 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

BackgroundAlthough the understanding of CYP2D6 developmental pharmacogenetics in children has made great progress, the current findings are mainly focused on Caucasian children. Given the clear ethnicity difference of CYP2D6 pharmacogenetic profile, there are still unmet needs in understanding developmental pharmacogenetics in inter-ethnic population. We sought to use loratadine as a probe drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese paediatric patients.MethodsChinese children receiving loratadine treatment were enrolled in the present study. The metabolic ratio (MR) of loratadine converted to desloratadine [desloratadine concentrations/loratadine concentrations] of trough concentrations samples at steady-state condition was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method and variants of CYP2D6 were genotyped.ResultsA total of 40 patients were available for final analysis. The mean age was 4.6 (range 0.5–9.0) years and the mean weight was 19.9 (range 9.0- 42.0) kg. The MR was significantly higher in homozygous wild-type subjects compared with CYP2D6*10 subjects (16.94±14.12 versus 9.37±7.54, p = 0.028). Weight was also found to be significantly corrected with MR (p = 0.030).ConclusionsThe developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a probe drug. Weight and CYP2D6 genotype showed independently significant impacts on MR.Disclosure(s)Nothing to disclose.
P112 Prediction of free Ceftriaxone concentration in children: disease and maturation do matter
Authors: Shi H-Y , Huang X , Li Q , Y-E Wu , Khan MW , Zhou Y , Zheng Y , Hao G-X , Yang X-M , Yang Y-L , Jacqz-Aigrain E , Cui Y-M , Zhao W 
Published: May 2019

BackgroundTo evaluate the predictive ability of the existing formula to measure free ceftriaxone levels in children, and optimize the formula by adding disease and maturation factors.MethodsFifty children receiving ceftriaxone were evaluated, and the predictive performance of the different equations were assessed by mean absolute error (MAE), mean prediction error (MPE) and linear regression of predicted vs. actual free levels.ResultsThe average free ceftriaxone concentration was 2.11 ± 9.51µg/ml. The predicted free concentration was 1.15 ± 4.39µg/ml with the in vivo binding equation, which increased to 1.58 ± 7.73µg/ml and 2.01 ± 9.53µg/ml when adjusted for age (disease adapted equation), and age and albumin (disease-maturation equation) respectively. The average MAE values were 0.48 (in vivo banding equation), 0.34 (disease adapted equation) and 0.41 (disease maturation equation). The average MPE values were -0.41 (in vivo binding equation), 0.14 (disease adapted equation) and 0.09 (disease maturation equation). The respective linear regression equations and coefficients were y=1.8647x+1.0731(R2=0.7398), y=1.1455x+0.8414(R2=0.8674), and y=0.9664x(R2=0.8641) for the in vivo binding, disease adapted and disease maturation equations respectively.ConclusionCompared to the in vivo binding equation, the disease adapted and disease maturation equations showed lower MAE and MPE values, and the latter showed the lowest MPE value. In addition, the slope of the disease maturation equation was closer to 1 compared to the other two. Therefore, the optimized disease maturation equation should be used to measure free ceftriaxone levels in children.Disclosure(s)Nothing to disclose.
P114 Population pharmacokinetics and dosing optimization of cefepime in neonates
Authors: Zhao W , Group TINN-Global Study 
Published: May 2019

ObjectiveCefepime, a fourth-generation cephalosporin, is used in the treatment of severe nosocomial infections in neonates. Pharmacokinetics of cefepime was limited. Therefore, we aimed to study the population pharmacokinetics of cefepime and optimize cefepime regimen in preterm and term neonates.MethodsBlood samples were obtained from neonates treated with cefepime using an opportunistic sampling design. Concentration of cefepime was determined by high performance liquid chromatography. Population pharmacokinetics analysis was conducted using NONMEM software.ResultsSparse pharmacokinetic samples (n=100) from 85 neonatal patients were available for analysis. A one-compartment model with first-order elimination was used to describe the pharmacokinetics of cefepime. Covariate analysis showed that current weight, postmenstrual age and serum creatinine concentration had tremendous influence on pharmacokinetics of cefepime. Monte Carlo simulation indicated that current dosage regimen (30 mg/kg, q12h) was correlated with high risk of underdosing in neonates. To achieve the target rate of 70% of patients get free drug concentration above MIC during 70% of dosing interval, 30 mg/kg q8h was required for all neonates, using susceptibility breakpoint of 4 mg/L.ConclusionThe population pharmacokinetics characteristics of cefepime were evaluated in neonates. Based on simulation, different dosage regimens were required depending on the postmenstrual age and pathogens.Disclosure(s)Nothing to disclose.
O17 The bioavailability and maturing clearance of doxapram in preterm infants
Authors: Flint RB , Simons SHP , Andriessen P , Liem KD , Degraeuwe PLJ , Reiss IKM , Ter Heine R , Engbers AGJ , Koch BCP , De Groot R , Burger DM , Knibbe CAJ , Völler S ,   DINOResearch Group
Published: May 2019

BackgroundDoxapram is used for intravenous and oral treatment of apnea of prematurity in preterm infants. Dosing is currently based on bodyweight, however pharmacokinetic and bioavailability data are limited. To develop individualized dosing strategies, we characterized pharmacokinetics of doxapram in this vulnerable patient population.MethodsData (302 samples) from 75 neonates were included with median (range) gestational age (GA) 25.9 (23.9–29.4) weeks, bodyweight 0.95 (0.48–1.61) kg, postnatal age (PNA) 17 (1–52) days at start of continuous treatment, and treatment duration of 16.8 (1.4–26.9) days. A population pharmacokinetic model was developed for doxapram and keto-doxapram.ResultsA two-compartment model best described the pharmacokinetics of doxapram and its metabolite. PNA and GA affected the formation clearance of keto-doxapram (CLD-KD) and clearance of doxapram via other routes (CLD). For an individual of 0.95 kg, GA of 25.9 weeks and PNA of 17 days, CLD-KD was 0.096 L/h (residual standard error (RSE) 22%) and CLD0.493 L/h (RSE 13%). Compared to PNA 30 days, estimated CLD-KD was 13% at PNA day 1 and 69% at day 15, and estimated CLD was 12% and 68%, respectively. Compared to GA 28 weeks, estimated CLD-KD was 65% at GA 24 weeks and 80% at 26 weeks, and estimated CLD was 67% and 81%, respectively. Oral bioavailability was estimated 74% (RSE 13%).ConclusionsWith bodyweight-based dosing alone, preterm infants with the lowest PNA and GA had relatively low doxapram CL and the highest exposure. Therefore, the dose may be reduced by 50% up to PNA day 9, and by 25% for day 10–15. In addition, for GA dose may be reduced by 40% and 20% in newborns with GA of 24–25 weeks and 26–27 weeks, respectively, compared to 28–29 weeks. For switch to oral therapy a 33% dose increase is required to maintain plasma concentrations.Disclosure(s)Nothing to disclose
O29 Pharmacometric modelling of free thyroxine dynamics after initiation of antithyroid drug treatment in children with Graves’ disease: a tool for personalized drug dosing in children
Authors: Koch G , Gotta V , Ollagnier C , Konrad D , Flück C , L’Allemand D , Steigert M , Rohner A , Bachmann F , Schropp J , Szinnai G , Pfister M 
Published: May 2019

BackgroundThyroid hormones are essential for normal growth and puberty in children and adolescents. Graves’ disease (GD) is a rare autoimmune disorder associated with thyroid hormone over-production and occurs in 0.5–2:100’000 children (mostly females) in Europe. In contrast to adults, first line treatment of GD is long-term antithyroid drug (ATD) therapy, and radioiodine ablation is usually being reserved for patients after puberty. However, treatment of acquired hyperthyroidism with ATD is difficult since 1) paediatric patients differ considerable in age, weight and diseases severity and 2) minimal ATD dose should be used to avoid mild side effects (occurring in 6–35% of patients), and rare severe side effects such as agranulocytosis and liver failure.MethodsLongitudinal clinical and laboratory data from a Swiss multicentre cohort were analysed retrospectively. Non-linear mixed effects modelling was applied to characterize dynamics of free thyroxine (FT4) during the first 3 months of treatment with carbimazole. Sex, co-medications such as propranolol, and thyroid stimulating hormone receptor antibody were tested as covariates on model parameters. Reference range for FT4 was derived from target levels in clinical practice (12–22 pmol/L).ResultsStudy cohort comprised 45 children with GD, 78% females, median age 12.2 years (IQR = [8.7,13.6])) with a total of 181 visits. FT4 baseline at diagnosis of GD was 62.3 pmol/L (IQR = [45.7, 86.7]). None of the tested factors showed significant covariate effects. The model allows individual simulations of optimal ATD dosing strategies (starting and maintenance dose) for different GD severities, ages and weights at start of therapy. Personalized dosing examples will be presented.ConclusionsDeveloped pharmacometric model is able to predict dynamics of FT4 in children with GD depending on four parameters: ATD dose/kg/d, age, weight and disease severity, and can be applied to personalize dosing regimen to avoid over- or under dosing.Disclosure(s)Nothing to disclose