bluuebunny/crossref_metadata_2025 huggingface dataset:
P114 Population pharmacokinetics and dosing optimization of cefepime in neonates
Authors: Zhao W , Group TINN-Global Study
Published: May 2019

Objective

Cefepime, 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.

Methods

Blood 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.

Results

Sparse 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.

Conclusion

The 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

Background

Doxapram 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.

Methods

Data (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.

Results

A 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%).

Conclusions

With 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

Background

Thyroid 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.

Methods

Longitudinal 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).

Results

Study 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.

Conclusions

Developed 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
O03 Allergy to penicillins in a pediatric population: reported vs true
Authors: Elzagallaai AA , Gill H , Rieder MJ
Published: May 2019

Background

Reported 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.

Objectives

To 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.

Methods

Paediatric 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).

Results

Ninety 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).

Conclusions

True 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

Background

Postnatal 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.

Results

Expression 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.

Conclusion

Renal 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

Background

Anti-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.

Objective

To monitor LEV levels in breast-milk of epileptic mothers treated with LEV.

Methods

Breastfeeding 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.

Results

Fourteen 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.

Conclusions

Although 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

Background

Midazolam 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.

Methods

Trial 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).

Results

Seventy-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.

Conclusion

BMI 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.

References

Smith 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

Background

Physiologic 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.

Methods

PBPK 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.

Results

In 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.

Conclusion

These 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.

References

Frenkel 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

Background

The 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.

Objectives

To follow up fetal outcome after gestational exposure to DYD.

Patients and methods

Using 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).

Results

There 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)].

Conclusions

DYD 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

Background

Tenofovir 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.

Methods

A 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.4

Results

In 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 0.60.4

Conclusion

The 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.

References

Abduljalil, et al. Clin Pharmacokinet 2018;57(9):1149–1171.

Abduljalil, et al. Clin Pharmacokinet 2019;58:235–262

Gilead 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

Background

Protocol 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.

Methods

Pubmed, 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.

Results

RA 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.

Conclusions

In 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.

References

Bozic 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

Background

Qualitative 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.

Methods

The 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.

Results

During 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.

Conclusions

The 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
P21 PBPK modeling in pregnancy: achievements, shortcomings and future perspectives
Authors: Dallmann A , Mian P , Annaert P , Pfister M , Allegaert K , van den Anker J
Published: May 2019

Background

Physiologically-based pharmacokinetic (PBPK) models are considered a promising approach to better characterize and anticipate the effect of physiological changes on pharmacokinetics in pregnant women. Consequently, multiple pregnancy PBPK models have been developed and verified over the past years. Using acetaminophen (paracetamol) as example, PBPK modeling can provide specific insights into the expected pharmacokinetic changes throughout pregnancy.

Methods

To obtain an overview of pregnancy PBPK models, the scientific literature was systematically screened for publications with a focus on pharmaceutical applications using relevant keywords. Additionally, a pregnancy PBPK model for acetaminophen was developed with the Open Systems Pharmacology software suite (www.open-systems-pharmacology.org) following an established workflow. After model verification around gestational week 30, the model was scaled to earlier stages of pregnancy and molar dose fractions converted to acetaminophen metabolites were estimated for each trimester.

Results

Over the past years, more than 60 different pregnancy PBPK models for more than have 40 drugs been published. More than 70% of these models were developed for the third trimester, while few models have been applied to the first trimester. The developed PBPK model for acetaminophen indicated that the median dose fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI) was 11%, 9.0% and 8.2% in the first, second and third trimester, respectively, while for non-pregnant women a value of 7.7% was simulated.

Conclusion

While the overall availability and quality of pregnancy PBPK models is varying considerably, the efforts to establish such models are promising in that they reflect an increased awareness of the necessity to better characterize pharmacokinetics during pregnancy. This is illustrated by the developed PBPK model for acetaminophen where information on NAPQI-formation in vivo is hitherto lacking. Although PBPK models are not a substitute for clinical trials, they constitute an important tool for clinicians in case of missing or incomplete information.

Disclosure(s)

Nothing to disclose
O06 Methadone dosing strategies in preterm neonates can be simplified
Authors: van Donge T , Samiee-Zafarghandy S , Pfister M , Koch G , Kalani M , Bordbar A , van den Anker J
Published: May 2019

Aims

A dramatic increase in newborn infants with neonatal abstinence syndrome has been observed and these neonates are frequently treated with complex methadone dosing schemes to control their withdrawal symptoms. Despite its abundant use, hardly any data on the pharmacokinetics of methadone is available in preterm neonates. Therefore we investigated developmental pharmacokinetics of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population.

Methods

A single center open-label prospective study was performed to collect pharmacokinetic data after a single oral dose of methadone in preterm neonates. A population pharmacokinetic model was built to characterize developmental pharmacokinetics of methadone and to assess the effects of weight and age on clearance and volume of distribution. In addition, simulation techniques were applied to evaluate reported dosing scenarios, investigate methadone exposure levels and examine the feasibility of simplified dosing recommendations.

Results

In total, 121 methadone concentrations were collected from 31 preterm neonates. The median weight and gestational age amounted 1.6 kg and 32 weeks, respectively. A one-compartment model with first order absorption and elimination kinetics best described the data for (R)- and (S)-methadone. Clearance was observed to be higher for the (R)-enantiomer as compared to the (S)-enantiomer (0.244 versus 0.167 L/h). Target exposures, based on simulations, can be maintained with a simplified dosing strategy during the first four days of treatment. It is therefore questionable if there is a need for the currently used more extended dosing regimen of methadone in neonates.

conclusions

This clinical investigation demonstrates that the clearance of methadone increases with advancing gestational age and higher clearance values and volumes of distribution can be observed for (R)-methadone as compared to (S)-methadone in preterm neonates. Simulations that account for developmental pharmacokinetics indicate that a simplified methadone dosing strategy can maintain target exposure to control withdrawal symptoms in preterm neonates.

Disclosure(s)

Nothing to disclose
P22 ADME properties of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug
Authors: Damsker JM , Piyis Y , Peña LA , McCall JM
Published: May 2019

Background

Vamorolone is a first-in-class dissociative steroidal drug currently in Phase 2b/3 clinical trials in four to seven-year old boys with Duchenne muscular dystrophy (DMD). Recent published findings from a Phase 2a study in DMD boys have demonstrated that vamorolone is well-tolerated through the highest dose tested (6 mg/kg/day; two-weeks treatment) and shows a similar pharmacokinetic profile to prednisolone.1 The objective of the current study was to assess the ADME (absorption, distribution, metabolism, excretion) properties of vamorolone using in vivo quantitative whole-body autoradiography (QWBA) and mass balance experimentation in rats.

Methods

For the QWBA study, Long Evans (LE) rats were dosed with 14C-labeled vamorolone and sacrificed after a defined time interval (6 groups with n=5 rats per time interval). Each frozen rat carcass was embedded in a carboxymethylcellulose matrix and cyrosectioned. Autoradiography images were acquired, analyzed, and the radioactivity in each tissue was quantified. For the mass balance study, LE rats (n=6) were dosed with 14C-labeled vamorolone. Urine and feces were collected from each animal at defined time intervals.

Results

The QWBA study demonstrated a widespread distribution of vamorolone amongst body organs with a peak absorption between 2–6 hours for most structures. In gastrointestinal tract organs, the peak absorption fell between the 6 and 24-hour time points. The mass balance study revealed that vamorolone was eliminated to low steady state levels by 5 days post administration in urine and 7 days post administration in feces.

Conclusions

This study provides crucial information regarding the ADME properties of vamorolone. The results will help guide the design of a human mass balance study scheduled to take place in late 2019 or early 2020.

Reference

Conklin LS, Damsker JM, Hoffman EP, et al. Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. Pharma Res. 2018; 136: 140–150.

Disclosure(s)

Jesse M. Damsker and John M. McCall are employees of ReveraGen BioPharma Inc. and have stock options and founder shares, respectively.
O07 Predictive performance of a physiologically based pharmacokinetic model of caffeine in the preterm population
Authors: Pansari A , Abduljalil K , Johnson T
Published: May 2019

Background

Caffeine has been extensively used in the treatment of apnoea in premature infants,1 its disposition varies with postnatal age2 and can differ markedly between premature and term neonates.

Methods

The Preterm population within the Simcyp Simulator V18R1 population library was used to replicate clinical studies to predict caffeine exposure after single3 and multiple4 intravenous administration to preterm neonates of gestational weeks 28.5 and 29 (28–33) respectively, ranging in postnatal age of 3–30 days and 0–3 days respectively. Predictive performance of the Physiologically Based Pharmacokinetic Model (PBPK) was evaluated by comparing the simulated to the clinical results. A population simulation was performed for the single dose study as only pharmacokinetic parameters were available. However, for multiple doses study, where individual plasma concentration-time profile data were available, simulations were performed for each individual.

Results

PBPK model predictions for caffeine in preterm neonates were in good agreement with the clinical observations. In the case of single dose administration, the ratios of predicted vs observed mean Volume of distribution (Vss), peak plasma concentration (Cmax), Clearance (CL) and Half-life (t1/2) were 1, 1.2, 1 and 1.1, respectively. Individual predicted concentration-time profiles following multiple dose administration were in close agreement with the observed data for all 16 subjects, overall 95% of individual observed data points were within the 5th and 95th percentile of predicted plasma concentration-time profile.

Conclusions

The predictive performance of preterm PBPK models for caffeine was found to be appropriate. A similar PBPK approach can be utilized in the clinics for the accurate prediction of pharmacokinetic parameters and plasma concentrations and for dosage adjustment to attain specific plasma concentrations of drugs in premature population.

References

Giacoia, et al. Effects of formula feeding on oral absorption of caffeine in premature infants. Dev Pharmacol Ther 1989; 12:205–210.

Johnson, et al. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet 2006; 45(9):931–56.

Aranda, et al. Population Pharmacokinetic profile of caffeine in the premature newborn infant with apnea; The Journal of Pediatrics 1979; 94(4.):663–668.

Lee, et al. Caffeine in apnoeic asian neonates: a sparse data analysis. Br J Clin Pharmacol 2002; 54:31–37.

Disclosure(s)

Nothing to disclose
P48 Prescribing patterns of antiasthma medication in children and adolescents in primary care in france
Authors: Naiim I , Tubach F , Guillo S , Ajrouche A , Houdouin V , De Rycke Y , Kaguelidou F
Published: May 2019

Background

Little is known about the short and long-term therapeutic management of asthmatic children. The aim of this study was to assess the prescribing patterns of antiasthma drugs in primary care.

Methods

This is a retrospective cohort study performed between January 2011 and December 2017 using the EGB (Echantillon Généraliste de Bénéficiaires) database, a 1/97th sample of the French national healthcare insurance system. Claims data for all individuals aged from 5 to 18 years‘ old who had received at least one antiasthma drug in the study period without any delivery in the previous 24 months and with 24 months of follow-up after first delivery, were analysed.

Results

A total of 7,680 children and adolescents (68.6% aged 5–11, 31.4% aged 12–18 years) were delivered at least one antiasthma drug (ATC code R03) during study period. The majority (66%) did not redeem another prescription in the following year (occasional users), when 18.4% redeemed prescriptions twice (low users) and 15.6% ≥3 times (high users). Most users (67%) were delivered only one class of R03 per dispensing in the first year and short-acting β2-agonists (SABAs) were the most frequently dispensed drugs. However, 33.4% of users were not prescribed SABAs. During the second year, only 27% of first-year users redeemed R03 prescriptions: 15.8% among occasional users, 35.5% of low users and 64.7% of high users. Among low and high first-year users who redeemed R03 drugs during the second year, 39.7% did not use inhaled corticoids alone or in association to LABAs.

Conclusions

A high proportion of children and adolescents that used antiasthmatic drugs, even on a regular basis, were not prescribed these drugs in the long term. This finding may correspond either to the widespread use of antiasthmatic drugs in indications other than asthma or to an important undertreatment of asthmatic children and adolescents.

Disclosure(s)

Nothing to disclose
P49 A pharmacokinetic evaluation of oral clavulanic acid in term newborns
Authors: Keij FM , Kornelisse RF , Hartwig NG , van der Sluijs J , van Driel A , Kenter S , Heidema J , den Butter P , Koch BCP , Reiss IKM , Allegaert K , Tramper-Stranders GA
Published: May 2019

Background

Clavulanic acid is an irreversible beta-lactamase inhibitor which has a weak antibacterial action. When combined with a beta-lactam antibiotic such as amoxicillin, it is effective against a broad range of bacteria. Despite its widespread use, little is known on the mechanism of action and target levels. A few studies on oral clavulanic acid in adults are available reporting great variance (AUC median 4.99 mg·h/L [0.44–8.31])1 and a short elimination half-time (1.08h).2 Observations in neonates are currently lacking. We therefore evaluated the pharmacokinetics of oral clavulanic acid co-administered with amoxicillin in term newborns.

Methods

As part of a multicenter RCT (Clinicaltrials.gov:NCT03247920) evaluating neonatal intravenous-to-oral switch therapy in probable bacterial infection, we measured serum levels in patients allocated to the intervention group. They switched to amoxicillin/clavulanic acid suspension (25/6.25 mg/kg tid), after 48 hours of intravenous penicillin/gentamicin. Two blood samples from different dosing intervals, were obtained and directly stored at -80°C. Initially, and to ensure that amoxicillin levels were attained as safety marker, levels in the second part of the timeframe (4–8 h after administration) were collected. For the second batch, peak levels (1–2 h after administration) were collected. Analysis was performed using Liquid Chromatography and Mass Spectrometry.

Results

At submission, samples of the first 15 patients were analysed (first batch). Samples were collected 6.0 ± 1.3 h (mean,S.D.) after antibiotic administration. Clavulanic acid levels were detected in all patients but a great variance was observed (median: 1.4 mg/L; range: 0.20–4.82 mg/L). Extrapolation would lead to an AUC of at least 8.4 mg·h/L.

Conclusions

Oral clavulanic acid is absorbed in term newborns, but great variance is seen in trough levels (4–8 h after administration). Extrapolation predicts at least an AUC comparable to those of adults. Peak levels in the first part of the time interval (0–4h) are needed to further build confidence on this conclusion.

References

De Velde F, De Winter BCM, Koch BCP, Van Gelder T, Mouton JW, Consortium C-N. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J Antimicrob Chemother. 2018;73(2):469–76.

Vree TB, Dammers E, Exler PS. Identical pattern of highly variable absorption of clavulanic acid from four different oral formulations of co-amoxiclav in healthy subjects. J Antimicrob Chemother 2003;51(2):373–8.

Disclosure(s)

Nothing to disclose
P50 Individual variations in fentanyl pharmacokinetics and pharmacodynamics in preterm infants
Authors: Kindblom J , Norman E , Rane A , Berg A-C , Schubert U , Hallberg B , Fellman V
Published: May 2019

Background

Fentanyl pharmacokinetics and pharmacodynamics are lacking in preterm infants. Our aim was to study these and their relation with a new formulation of fentanyl 5 mg/mL for procedural pain.

Methods

Preterm infants were given 0.5 (n=20, median gestational age 26.5; range 23.3–34.1 weeks) and 2 mg/kg (n=8, 27.4; 25.3–30.7 weeks) fentanyl, respectively, before skin-breaking procedures or tracheal intubation. Blood samples were collected after ten minutes, two, four, eight and 24 hours. Physiologic parameters were monitored and pain scores assessed.

Results

The median fentanyl concentrations were 0.18, 0.15, 0.15 and 0.57, 0.37, 0.35ng/mL at 15–31 minutes, two and four hours and the half-lives were 1.6 to 20.5 or 4.1 to 32.6 hours for the low and high dose groups, respectively. A significant correlation was seen between weight at study inclusion and half-life (Spearman´s r = -0.9, p< 0.001), volume of distribution (r = -0.8, p < 0.01) and clearance (r = -0.9, p < 0.01) in the low dose group (n=9). Pain assessment results were not correlated to pharmacokinetic variables. Fentanyl was well tolerated.

Conclusion

The inter-individual variation of fentanyl pharmacokinetics is large in preterm infants and the dose of 0.5 mg/kg seems too small for skin-breaking procedures.

Disclosure(s)

Nothing to disclose
P53 Exposure of infants to brominated flame retardants through breast-milk
Authors: Kohn E , Efreim S , Lubetzky R , Mandel D , Marom R , Betser M , Keidar R , Livne A , Levy A , Factor-Litvak P , Soback S , Britzi M , Berkovitch M
Published: May 2019

Introduction

Polybrominated Diphenyl Ethers (PBDEs) are non-biodegradable flame retardants, accumulated in biological systems and acting as endocrine disruptors. Breast feeding is a major route of exposure in infancy. Taken together with the critical development of this age and the potential adverse effects of PBDEs, it is important to monitor these contaminants in breastmilk.

Objective

To evaluate the exposure of infants to PBDEs

Methods

343 families were recruited during 2013–2016 in Assaf Harofeh and Ichilov to create the AHI-EHF cohort. Maternal blood and urine, cord blood, breast milk and meconium were collected. Participants filled out questionnaires about socio-demographic status, medical history, exposures and life habits. Colostrum samples were collected from women at the maternity department. PBDEs in colostrum and Infant formulas levels were analyzed using GC-MS

Results and discussion

Out of 183 serum samples, only 11(6%) detectable levels of PBDEs. PBDEs were found in all colostrum samples. The average concentration of total PBDEs in breastmilk was 714ng/L. PBDEs levels were also measured in three infant formulas. Unlike breastmilk, infant formulas had of only 3 congeners and levels were relatively low. The average concentration of total PBDEs in infant formulas was 153ng/L. PBDEs, were found to be negatively correlated to anno-penile index (API) which serve as a marker for endocrine disruption.

Conclusions

PBDEs levels in breast milk are higher than levels in some European countries, but lower than in North America. PBDEs might have negative influence on AGD in boys. Maternal exposure to PBDEs and the significance of it should be further investigated.

Disclosure(s)

Nothing to disclose