bluuebunny/crossref_metadata_2025_split huggingface dataset:
O03 Allergy to penicillins in a pediatric population: reported vs true
Authors: Elzagallaai AA , Gill H , Rieder MJ 
Published: May 2019

BackgroundReported allergy to penicillins is a major clinical problem. Over 10% of parents report drug allergy resulting in higher cost and less than optimum management of infectious diseases.ObjectivesTo determine the relative likelihood of true allergy in patients suspected to have a penicillin allergy and to investigate the risk factors involved. We hypothesized that the vast majority of self-reported penicillin allergies are less likely to be true allergies when proper immunological work up is performed.MethodsPaediatric patients aged 0–18 years presenting to the ADR clinic at the Children Hospital of Western Ontario (CHWO) with suspected antibiotic allergies were included. A retrospective review of charts was conducted to obtain demographic information and results from allergological and in vitro testing. Subjects were evaluated with a radioallergosorbent test (RAST) or the lymphocyte toxicity assay (LTA)/the invitro platelet toxicity assay (iPTA) depending on whether the history was most consistent with an immediate allergy or a delayed hypersensitivity, respectively. Patients with negative RAST or LTA/iPTA were recommended to undergo confirmatory oral challenge test (OCT).ResultsNinety subjects were identified including 75 with possible penicillin allergy and 10 with suspected allergy to a non-penicillin antibiotic. Five subjects presented with a mixed allergy. Based on the results from RAST, in vitro testing and OCTs, the prevalence of a true allergy in the penicillin group was 6.25% vs. 66.67% in the non-penicillin group (p< 0.001). Patients presenting with severe reactions were more likely to be truly allergic (p< 0.01). In-patients were more likely to present with non-penicillin allergies and were subsequently more likely to have a true allergy (p< 0.001).ConclusionsTrue allergy is very rare in patients with suspected penicillin allergies and can be determined with a proper work-up including OCT. Shorter protocols for the evaluation of these patients would be beneficial.Disclosure(s)Nothing to disclose
O30 A comprehensive analysis of ontogeny of renal drug transporters: mRNA analyses, quantitative proteomics and localization
Authors: Cheung KWK , van Groen BD , Spaans E , van Borselen MD , Bruijn ACJM de , Simons-Oosterhuis Y , Tibboel D , Samsom JN , Verdijk RM , Smeets B , Zhang L , Huang S-M , Giacomini KM , de Wildt SN 
Published: May 2019

BackgroundPostnatal developmental changes of human renal membrane transporters, which are key players of disposition of renally cleared drugs and endogenous substrates, are largely unknown. This study aimed to characterize the ontogeny of 11 human renal transporters to understand changes in the renal clearance of substrate drugs in children.Methods mRNA levels of known renal transporters: BCRP, MATE1, MATE2-K, MDR1, MRP2, MRP4, URAT1, GLUT2, OAT1, OAT3 and OCT2, and the transcription factor PXR were measured with RT-qPCR in 184 human postmortem frozen renal cortical tissues (preterm newborns - adults; 1 day-75 yrs old) from individuals of European and African descent. Protein expression of all but MRP2, MRP4 and PXR was quantified with LC-MS/MS SRM in 62 of those samples (term newborns - adults; 1 day-29 yrs old). Localization of MRP4 was tested with immunohistochemistry.ResultsExpression levels of MDR1, URAT1, OAT1, OAT3, and OCT2 increased with age, but levels of MATE1 and GLUT2 were stable from birth. Protein levels of MATE2-K and BCRP showed no difference from newborns to adults despite age-related changes in mRNA expression. MRP2, MRP4 and PXR expression levels were stable. MRP4 localization in pediatric samples was similar to that in adult samples.ConclusionRenal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of both endogenous and exogenous compounds may change with age. It is important to consider ontogeny of renal transporters during pediatric drug development.Disclosure(s)The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Views expressed in this paper are those of authors and do not necessarily reflect the official views or policies of the FDA; nor does any mention of trade names, commercial practices, or organization imply endorsement by the U.S. Government.*Contributed equally,**Contributed equally
O31 Levetiracetam monitoring in breast-milk: high inter-individual variability
Authors: Dinavitser N , Kohn E , Berlin M , Livne A , Keidar R , Ben-Nun L , Agajani N , Sheinberg R , Gamsu S , Flor-Hirsch H , Brandriss N , Bar-Chaim A , Stepenski D , Berkovitch M 
Published: May 2019

BackgroundAnti-epileptic drug therapy is a great challenge for the practitioners during pregnancy and lactation. Levetiracetam (LEV) is commonly prescribed to pregnant women, however, there are only few publications on its use during lactation with small number of participants.ObjectiveTo monitor LEV levels in breast-milk of epileptic mothers treated with LEV.MethodsBreastfeeding women treated with LEV during pregnancy and after delivery were recruited. Milk sample was collected before administration of the drug and other samples were collected at time points of 1,3,6,9, and 12 hours after drug administration. Breastmilk and blood LEV levels were measured using HPLC.ResultsFourteen breastfeeding women participated in the study: 9 infants were fully breastfed whereas 5 were partially breastfed. Maternal average daily dose of LEV was 2517 mg. Average infant´s age was 8 weeks (3–22w). Average infant´s weight 4368 gr (3300–7000 gr). Milk/Plasma LEV concentration ratio was 0.88 (0.23–1.1). Relative Infant Dose (RID) was 40% in partial breast feeding, and 61% in full breastfeeding. Estimated average daily dose that all infants received through milk was 158 mg/d (83–250 mg). The normalized dose for the average infant weight per day was 36 mg, which is 15% less than the maximal daily dose of LEV in infants (max. daily dose in infants 1–6 months in 42 mg/d). No adverse reactions were observed in the breastfeed infants.ConclusionsAlthough the RID of LEV were found to be high, no adverse reactions were observed in the infants; Nevertheless, further studies are needed to elucidate the high variability of LEV excretion into breastmilk.Disclosure(s)Nothing to disclose
O35 Midazolam pharmacokinetics in children with obesity
Authors: Gade C , Sverrisdóttir E , Dalhoff K , Sonne J , Rolighed Christensen H , Burhenne J , Mikus G , Holm J-C , Meldgaard Lund T , Holst H 
Published: May 2019

BackgroundMidazolam is a first-line drug for treatment of status epilepticus,1 2 both by buccal and intravenous administration. In children with obesity, the midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.The aim of the study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese children, aged 11–18 years.MethodsTrial subjects were divided into groups by Body Mass Standard Deviation Score (SDS). All children received 1 µg midazolam administered an intravenous bolus dose. Thirteen blood samples were collected per participant at prespecified timepoints over 9 hours. Plasma concentration-time data was fitted to pharmacokinetic models using non-linear mixed effects modelling (NONMEM, 7.4).ResultsSeventy-two children were enrolled in the study, of these 67 children were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The changes in pharmacokinetics in children with obesity were best described with a linear function of BMI SDS on inter-compartmental clearance and peripheral volume. Thus, the rate of distribution was faster, and the peripheral volume of distribution was larger in children with obesity as compared to non-obese children. Simulations revealed that long-term infusions based on total body weight, could lead to high plasma concentrations in children with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose showed that children with obesity may be at risk of subtherapeutic plasma concentrations.ConclusionBMI SDS was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current Danish dosing guidelines for status epilepticus (http://www.paediatri.dk), where midazolam dose is adjusted to total body weight or age, may lead to both supra- and subtherapeutic doses respectively, in children with obesity. However, confirmatory studies are needed.ReferencesSmith R, Brown J. Midazolam for status epilepticus. Aust Prescr. februar 2017;40(1):23–5.Ulvi H, Yoldas T, Müngen B, Yigiter R. Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol oktober 2002;23(4):177–82.Disclosure(s)Nothing to disclose
O36 Physiologically based pharmacokinetic models to predict fetal exposure to antiviral drugs
Authors: Liu X , Momper J , Rakhmanina N , van den Anker J , Green D , Burckart G , Best B , Mirochnick M , Capparelli E , Dallmann A 
Published: May 2019

BackgroundPhysiologic changes associated with pregnancy may have a large impact on drug disposition. The goal of this study was to build PBPK maternal-fetal models to predict the fetal exposure to antiviral drugs including emtricitabine and acyclovir.MethodsPBPK models were built in the Open Systems Pharmacology Software Suite version 7.3 (www.open-systems-pharmacology.org). The maternal-fetal PBPK model structure was developed in MoBi and exported to PK-Sim for population simulations. Placental transfer was parameterized based on data from ex vivo cotyledon perfusion experiments. The predictive performance of the PBPK models was evaluated via comparison with in vivo data. The pregnancy data for those drugs were from in vivo maternal and fetal blood samples taken at delivery.ResultsIn the acyclovir ex vivo experimental data simulation, the fitted was 0.056 L/h (95% confidence interval: 0.043 - 0.069 L/h) and the fitted was 0.49 (95% confidence interval: 0.39 - 0.59). The predicted ratio between acyclovir in vivo concentrations in the umbilical vein plasma and the maternal plasma ranged from 0.37 - 0.77, whereas the observed ratios were slightly higher and ranged from 0.61 - 1.1.1 The previously published, and CLpl (1.49 1/h) parameters2 were applied to the emtricitabine maternal-fetal PBPK model, and the emtricitabine concentrations in the umbilical cord were adequately predicted.ConclusionThese results increase the confidence in applying PBPK models to predict maternal and fetal drug exposure. Improved maternal-fetal PBPK models may streamline and accelerate the performance of pharmacokinetic and safety studies for drugs in pregnant women.ReferencesFrenkel LM, et al. Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 1991;164:569–76.De Sousa Mendes M, et al. Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. Brit J Clin Pharmacol 2016;81:646–57.Disclosure(s)The opinions expressed in this article are those of the authors and should not be interpreted as the position of the U.S. Food and Drug Administration or of the National Institutes of Health. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
O04 Fetal Outcome following Dydrogesterone Exposure in Pregnancy
Authors: Koren G , Gilboa D 
Published: May 2019

BackgroundThe progestin dydrogesterone (DYD) is widely used for threatened and recurrent miscarriages, as well as for dysfunctional bleeding, infertility and other obstetric and gynecological indications. While its apparent efficacy has been compared to other progestins, its fetal safety has not been investigated.ObjectivesTo follow up fetal outcome after gestational exposure to DYD.Patients and methodsUsing a 2.5 million patients´ database, we compared congenital malformations among babies exposed in utero to DYD between 1999 and 2016, to a control group not receiving this medication. We adjusted for concomitant exposure to in vitro fertilization (IVF) and to other forms of assisted reproductive technology (ART).ResultsThere were 8508 children exposed in uteo to DYD (4417 males, 4091 females) out of 777,422 live births. After excluding cases with concomitant exposure to IVF and other forms of ART, DYD was associated with increased risk for hypospadias [OR 1.28(95% confidence interval 1.06–1.55)], overall cardiovascular malformations [OR 1.18 (1.06–1.33)], spina bifida [OR 2.29(1.32–3.97] and hydrpcephalus [OR 2.04(1.28–3.25]. In additional analysis, including also those exposed to IVF and other forms of ART, there was also increased risk for cryptorchidism [1.37(1.19–1.58)] and congenital dislocation of the hip [OR 1.58(1.42–1.78)].ConclusionsDYD confers teratogenic effects after exposure to the recommended doses in pregnant women. Some of these adverse fetal effects are further augmented by concomitant use of IVF and other forms of ART. These independent teratogenic effects may have important implication for the child and family.Disclosure(s)Nothing to disclose
P01 Application of feto-placental-maternal physiologically-based pharmacokinetic model to predict tenofovir concentration during pregnancy
Authors: Abduljalil K , Johnson TN , Jamei M 
Published: May 2019

BackgroundTenofovir is a drug used in combination with other anti-HIV drugs to treat patients with HIV-1 infection. It is used during pregnancy to reduce the risk of HIV transmission to the child. The aim of this work is to use a Physiologically-Based Pharmacokinetic (PBPK) model for prediction of maternal and fetal tenofovir concentration at birth.MethodsA full Feto-Placental-Maternal PBPK model that includes placenta as a 3-comparment permeability limited organ and 14 compartments for different fetal organs was developed using physiological1,2 and drug specific parameters3 to predict tenofovir concentration in 50 virtual pregnant mothers at term after single administration of 600 mg of tenofovir disoproxil fumarate (272 mg tenofovir). The mechanistic model implemented using the Simcyp Lua interface within the Simcyp Simulator. Fetal as well as maternal tissue to plasma ratio values were predicted using the Rodgers & Rowland method with a scalar of 1.5. Predictions of tenofovir maternal and fetal plasma concentration were compared to reported observations.4ResultsIn spite of the large variability in the observed data, the model adequately replicated the maternal as well as fetal clinical observations.4 The placenta transfer by cotyledon was changed 10 times the mean reported value from perfusion experiment.5 All other model parameters were calculated using bottom-up approach.The maternal predicted-to-observed ratio for AUC24hr and Cmax was 1.13 and 1.08, respectively. The predicted fetal exposure was well predicted within the 5th and 95th percentiles and was 0.51 of maternal exposure (AUC24h), the reported value is 0.60.4ConclusionThe developed feto-placental-maternal PBPK models can be used to predict drug exposure in fetal organs during in utero growth. The inter-subject variability can be predicted incorporating both the drug physicochemical properties and system (placental, maternal and fetal) parameters.ReferencesAbduljalil, et al. Clin Pharmacokinet 2018;57(9):1149–1171.Abduljalil, et al. Clin Pharmacokinet 2019;58:235–262Gilead Sciences, Inc. Product Information: tenofovir disoproxil fumarate (VIREAD) tablets.Hirt D, et al., Clin Pharmacol Ther 2009; 85: 182–9.De Sousa Mendes, et al., Br J Clin Pharmacol 2016;81(4):646–57.Disclosure(s)Nothing to disclose
P11 Neonatal and paediatric protocol development and drug safety: points to consider for risk management and safety data collection
Authors: Aurich B , Elie V , Jacqz-Aigrain E 
Published: May 2019

BackgroundProtocol development for neonatal or paediatric clinical trials needs to take into account the age group specifics of the study population (e.g. pharmacokinetics, reference values for laboratory data and vital signs). Drug safety and risk management for neonatal/paediatric trials require an understanding of how these change throughout childhood. We were interested in reviewing and summarising the literature to identify publications which provide researchers with practical information of how the neonatal/paediatric drug safety profile informs age group specific safety data collection and risk management in the protocol.MethodsPubmed, Embase and regulatory authority (RA) websites were searched for publications up to 31/12/2018 for children (0–18 years). In addition, the bibliography of included publications was reviewed to identify additional publications.ResultsRA websites provided general and disease specific guidance on neonatal/paediatric clinical trials with sections relating to drug safety. No publication was identified describing the practicalities of how the neonatal/paediatric drug safety profile can be included throughout the various sections of a clinical trial protocol. The existing literature was summarised providing an overview of how the neonatal/paediatric drug safety profile supports the development of the various protocol sections. For example laboratory values in the exclusion criteria and safety monitoring sections need to be adjusted for age. Vital sign and psychomotor assessment should be done at least at baseline, trial completion and follow-up. Monitoring of adverse events of interest requires consideration of how these may present in neonatal/paediatric patients.ConclusionsIn order to support the protocol development with regards to neonatal/paediatric drug safety a dual competence in both paediatrics and drug safety is required. This review provides an overview of the practical aspects related to neonatal/paediatric drug safety during protocol development.Disclosure(s)Nothing to disclose
P12 Public antibiotic awareness campaign organised by government significantly reduced inappropriate antibiotic use in paediatric primary care settings
Authors: Bajcetic M , Lazic M , Lukic I , Rajkovic D 
Published: May 2019

Serbia, like most other countries in southern Europe, has struggled with high rate of antibiotic consumption. Previous results showed that most of antibiotics were prescribed inappropriately, mainly for influence - like illness1. The first short term media antibiotic awareness campaign (AAC) was held in 2011. and 2014. respectively. Shortly after, Ministry of Health, Republic of Serbia in November 2015 has started with public AAC simultaneously across all regions of Republic of Serbia.Apart from media, the campaign included education, producing national guidelines, as well as regulations. The education goals for public (preschool and school children, parents, pregnant women, students) and healthcare professionals (paediatricians, nurses, pharmacists, etc.) was based on results of analysis of antibiotic consumption in children from 2007.to 2014. which methodology was published previously.1 Media campaign included public relations activities, press conferences, billboards, printed materials, etc.In 2017. prescribing rates of antibiotics per 1000 children in primary care settings were decreased by 18% comparing to 2011., after first and by 12% comparing to 2014. when second short term media campaign was performed. After the third, government organised public AAC, prescribing rates of antibiotics per 1000 children in primary care settings were decreased by 6% for only one year (2017 vs. 2016) in all age groups from 2 months up to 17 years. Significant decrease of prescribed rate of antibiotics per 1000 children during 2017. was recorded for indication with policy of delayed or no antibiotic prescription recommended by guidelines. Seasonal oscillations showed that highest prescribing rate during the winter months (I and the IV quarter) of 2017. is in line with the lowest prescribing rate during the summer months (II and the III quarter) from 2007. up to 2013.We can conclude that continuous antibiotic awareness campaign supported by state government is the best way to achieve successful results.ReferencesBozic B, Bajcetic M. Use of antibiotics in paediatric primary care settings in Serbia. Arch Dis Child 2015 Oct;100(10):966–9.Disclosure(s)Nothing to disclose
P18 Appropriateness of antibiotic prescriptions for children and adolescents attending emergency departments for pharyngotonsillitis
Authors: Messina F , Clavenna A , Cartabia M , Bortolotti A , Fortino I , Merlino L , Bonati M 
Published: May 2019

BackgroundQualitative and quantitative differences in the antibiotic prescription profiles for paediatric outpatients have been found between and within countries, and Italy has a high prevalence of prescriptions and frequent use of cephalosporins and macrolides. Scant data, on small samples, are available concerning the prescription profiles in emergency departments (ED), also in Italy.MethodsThe data sources were administrative healthcare databases of the Lombardy region (16% of the national paediatric population).Children and adolescents between 1 and 13 years old with an ED access and an antibiotic prescription in the first semester of 2012 represented the target population. Subjects with ED access, hospital admissions, or antibiotic prescriptions in the previous two months were excluded, and the analyses were focused on children visited for pharyngotonsillitis.The percentage of subjects receiving amoxicillin (first-choice antibiotic) and the percentages receiving macrolides or cephalosporins (second-choice therapies) were estimated.ResultsDuring the observation period 23,216 children attended the ED for upper respiratory tract infections, 9,611 of which were visited for pharyngotonsillitis. In all, 5,427 (56%) children with pharyngotonsillitis received an antibiotic prescription: 24% were given amoxicillin and 18% received macrolides or cephalosporins. The percentage of children treated with amoxicillin decreased with increasing age (from 31% in 1–2 year olds to 15% in 10–13 year olds). On the contrary, the prescription of second choice treatments increased with age, reaching 23% in children 10–13 years old. Only in 5 out of 56 EDs more than half of children with pharyngotonsillitis received amoxicillin, while in 5 other EDs the first-choice antibiotic was never prescribed.ConclusionsThe under-prescription of amoxicillin highlights the low compliance with national and international guidelines on pharyngotonsillitis management. More must be done to improve rational use of antibiotics in the ED setting, and educational interventions are strongly needed.Disclosure(s)The study was partially funded by Lombardy Region (EPIFARM project). None of the authors has conflict of interest to disclose