bluuebunny/crossref_metadata_2025 huggingface dataset:
P63 UPLC/MS/MS assay for the simultaneous determination of seven antibiotics in human serum – application to pediatric studies
Authors: Magreault S , Chaussenery-Lorentz O , Storme T , Jacqz-Aigrain E
Published: May 2019

Background

Antimicrobials are widely used in children but pediatric dose regimens are not always validated, and PK studies, required to validate dosage, are difficult to conduct in children. Low sampling volume limits the number of PK samples drawn per patient and analytical methods adapted to small volumes are not always available. Due to the wide inter-patient pharmacokinetic (PK) variability in children, particularly neonates, therapeutic drug monitoring is required to adapt dosage to individual patients. In such clinical and analytical context, our aim was to develop a unique, rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay to quantify 7 antibiotics (amoxicillin, azithromycin, cefotaxime, ciprofloxacin, meropenem, metronidazole and piperacillin) in low sample volumes (50 µL) for both routine monitoring and pharmacokinetic studies.

Methods

After protein precipitation by acetonitrile, the antibiotics and their associated deuterated internal standard were separated on a Waters Acquity UPLC HSS T3 (100 mm x 2.1 mm; 1.8 µm). The mobile phases consisted of a gradient of ammonium acetate (pH 2.4; 5mM) and acetonitrile acidified with 0.1% (v/v) formic acid (started ratio of 93:7, v/v), run at 0.5 mL/min flow rate (total run time: 2.75 min). Ions were detected in the turbo-ion-spray-positive and multiple-reaction-monitoring modes.

Results

This method was linear from 0.1–50 µg/mL. Accuracy and precision were evaluated using Quality Control (2, 10, 35 µg/mL). Validation of the method proved that precision, selectivity and stability were all within the recommended limits.

Conclusion

This method has the advantage of a unique, efficient and standardized analytical tool for rapid measurement of 7 antibiotics in low blood volume. It has been successfully applied for routine activity and pharmacokinetic studies in children and neonates.

Disclosure(s)

Nothing to disclose.
P64 Quality assessment for the continuous bioanalysis of aldosterone: application in an European paediatric study
Authors: Makowski N , Burdman I , Ali M , Majid H , Farahani S , Ciplea AM , Bartel A , Burckhardt BB
Published: May 2019

Background

A validation is crucial to ensure the quality of an analytical method and its results. However, the validation is only a first step, further quality assessment has to be utilised to ensure high quality research. Specifications for the validation process, but also for the assessment of data, acquired in a study setting, are given by the EMA and FDA to ensure highest quality of the data.1 2

Methods

A multi-level analytical quality system was established. Data of the calibration standards (CSs), quality control samples (QCs), and incurred sample reanalysis (ISR) were evaluated according to the specifications given by the EMA and FDA guidelines.[1,2] For a run to be considered valid ≥6 levels or 75% of the CSs and 67% of the QCs (≥50% per level) had to vary ≤±20% (LLOQ ≤±25%) from their nominal concentration.[1,2] For the ISR analysis at least 67% of the ISR samples have to lay in ±30% to the nominal concentration of the mean of the original and reanalysed value.[1]

Results

Seventy analytical runs were conducted, applying the quality measures, 79% runs were classified as valid and were used to determine unknown samples in a paediatric study. The high quality of the acquired data is reflected in the high conformity of the CSs and QCs to the EMA and FDA guidelines, 99% of the CSs and 95% of the QCs were accepted. Further underlining the high quality of the acquired data, 85% of the IRS have also been accepted. The assay was successfully used over a time period of 29 months.

Conclusion

The results of the quality assessment confirmed the robustness of the aldosterone assay throughout the whole study duration. Thus, the samples measured by this assay are reliable and facilitate the high quality research in the paediatric population.

References

Guideline on bioanalytical method validation. European Medicines Agency, London, UK (2011).

Guidance for Industry: Bioanalytical Method Validation. US Department of Health and Human Services, US FDA Rockville, MD, USA (2018).

Disclosure(s)

Nina Makowski, Ilja Burdman, Mohsin Ali, Bartel A, Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
P77 Pediatric drug data in Canadian drug monographs
Authors: Patel A , Duffett M , Mazer-Amirshahi M , Raja P , Chan A , van den Anker J , Samiee-Zafarghandy S
Published: May 2019

Background

Optimal drug therapy in children relies on availability of pediatric-specific information. European and American legislative initiatives have resulted in advancement of pediatric pharmacotherapy data. We aim to describe the quality and quantity of pediatric information in drug monographs of New Active Substances (NASs) approved by Health Canada.

Design/Methods

Canadian drug monographs of NASs approved by Health Canada, from January 2007 until December 2016, were systematically reviewed for pediatric-specific information. Pediatric-specific information defined as: pediatric indication, dosing, pediatric-friendly dosage forms, and pediatric safety data.

Results

Over the period of the study, Health Canada approved 281 NASs. Of all the non-biologic NASs (205, 74%), 39(19%) were approved for use in pediatric patients. The number of drugs with pediatric approval was lowest in 2008 (1, 8%) and highest in 2016 (8, 32%), following no specific pattern. Neonates had the lowest rate of drug approvals through all pediatric age groups (4, 2%). All drugs with pediatric approval had pediatric-specific dosing information with the majority of them presenting pediatric safety data (79%). Pediatric friendly formulation was only available in 20%(8) of drugs with pediatric approval. Studies in pediatric populations were the source of pediatric information in 59%(23) of drugs with pediatric approval.

Conclusion(s)

Less than 20% of the NASs approved by Health Canada for use in adults contain pediatric approval. Neonatal populations remain a therapeutic orphan, with severe lack of dosing and safety information. Safe and effective pediatric pharmacotherapy requires well-conducted pediatric research to enhance pediatric drug data. Canadian children are in need for legislative initiatives to promote pediatric drug development.

Disclosure(s)

Nothing to disclose
P86 Treatment modalities in peripheral facial nerve palsy in children and adolescents
Authors: Samardzic J , Kukolj B , Jovanovic M , Djuric O , Jancic J
Published: May 2019

Background

Bell´s palsy is the most common type of peripheral facial palsy in pediatrics. Recent studies strongly support the combined therapy with corticosteroids (CS), antiviral drugs and vitamins B. Our study aims to assess the effectiveness of proposed therapeutic modalities, including the relation between the patients‘ recovery and their age, etiological factors and applied treatment.

Methods

The retrospective analysis involved 88 patients (52 females/36 males), between 18 months and 18 years old; the average age was 11.7 years. Data was obtained from the documentation of patients hospitalized at the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade, from 2000 to 2017. House Brackmann´s scale was used for the assessment of disease course and outcome. Pearson´s χ2 test, Friedman´s test and general linear model were applied for statistical data processing.

Results

The majority of patients were treated with combined CS/vitamins (42.0%) and CS/antiviral/vitamins (17.0%), whereas CS only received 22.7% of patients, all with an appropriate physical treatment. The group of idiopathic paralysis makes 62.5%, while the incidence of symptomatic paralysis is 37.5%; however, the recovery rate between these groups has not been shown (p=0.309). Patients received CS therapy were divided into 4 groups: CS only, CS+antiviral, CS+vitamins B, and CS+antiviral+vitamins B. The statistically significant recovery was registered in each group (p< 0.001); however, no difference was found between the groups in term of recovery rate (p=865). For the assessment of recovery period in relation to the age, the obtained p value was 0.054, a borderline level, suggesting a faster recovery of children at younger age.

Conclusion

The acute one-sided mimic musculature weakness is mostly idiopathic. The effectiveness of the CS therapy was strongly supported, suggesting CS as a core treatment for the Bell´s palsy. It has been shown the faster recovery of children at younger age.

Disclosure(s)

Nothing to disclose
P94 Reliable acquisition of plasma renin activity in the maturating renin-angiotensin-aldosterone-system by a validated small-volume assay in context of the LENA project
Authors: Suessenbach FK , Feickert M , Tins J , Burckhardt BB
Published: May 2019

Background

Physiological and pathophysiological circumstances of the paediatric renin-angiotensin-aldosterone-system (RAAS) are still inadequately understood. Due to the limited paediatric data available, the LENA (Labeling of Enalapril from Neonates up to Adolescents) project aimed to comprehensively investigate the drug enalapril and its effect on humoral parameters of the RAAS. Examination of four humoral parameters, including plasma renin activity (PRA), was conducted regarding cardiac diseased paediatric population receiving enalapril, of which 60% were below 1 year of age. To fully address the agreed Paediatric Investigation Plan (EMEA-001706-PIP) of the LENA project, reliable small-volume assays for pharmacodynamics determination were mandatory to ensure the reliable data sets.

Materials and methods

A commercial PRA enzyme linked immunosorbent assay (ELISA) was tailored for paediatric application and validated according to European Medicine Agency (EMA) and U.S. Food and Drug Administration (FDA) bioanalytical guidelines.1 2 In this context, accuracy, precision, total error, linearity, parallelism, matrix effects and stability were investigated.

Results

The adopted bioanalytical PRA-assay was successfully validated. Between-run precision (CV) and accuracy (relative error) ranged from 1.6% to 19.6% and -13.0% to +11.2% respectively. Samples of five different human sources showed no substantial matrix effect and facilitated the assay’s application to heterogeneous populations. The obtained precision of parallelism of five dilution steps ranged from 7.7% to 8.3% allowing to dilute high samples within the calibration range. Stability measurements proved four freeze and thaw cycles plus short-term and long-term (37 weeks) stability. Overall, all results were complied with guideline requirements.

Conclusion

The FDA/EMA-compliant PRA assay is able to accurately and precisely quantify PRA values in 50 µL plasma and is applicable for GCLP-compliant clinical studies enabling sophisticated investigations in children within the LENA project.

References

Committee for Medicinal Products for Human Use (CHMP): EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2** Guideline on bioanalytical method validation, June, 2015

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM): Bioanalytical Method Validation Guidance for Industry, May 2018

Disclosure(s)

Fabian K. Suessenbach, Martin Feickert, Jutta Tins and Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
P98 Semi-quantification and localization of membrane transporters in paediatric kidney tissue
Authors: van Borselen M , van Groen B , Pertijs J , Wilmer M , Smeets B , Verdijk R , de Wildt S
Published: May 2019

Background

The kidney has a critical role in disposition, efficacy and toxicity of drugs and xenobiotics. Developmental changes of renal membrane transporters have the potential to explain population variability in paediatric pharmacokinetics and -dynamics of drugs but data are missing. We aimed to further delineate the expression of human renal tubular transporters multidrug resistance-associated protein (MRP) 4 and MRP2 and study localization in paediatric kidney samples.

Methods

We planned to semi-quantify expression levels and to study the age-specific localization of the transporters MRP4 and MRP2 with immunohistochemistry on 44 human neonatal and paediatric kidney samples with age range of 24,00 - 40,00 weeks gestational age (GA) and 0,29 - 744 weeks post-natal age (PNA). The staining intensity was semi-quantitatively scored by two independent observers (MB and BG).

Results

MRP4 is found to be localized at the apical membrane of the renal proximal tubules at 27 weeks of GA (n=3, 1,29- 4 weeks PNA) and no age-related changes of expression levels were detected. In a premature neonate of 24 weeks GA (n=1), no MRP4 was detected. The MRP2 staining did not meet the requirements to be scored and was rejected.

Conclusion

MRP4 is expressed from at least 27 weeks GA onwards and does not show developmental changes. The localization was similar as in adults (Ritter et al., 2005). The half-life of the MRP4 substrate furosemide was found to be 6 to 20-fold longer in neonates than in adults (Pacifici, G.M., 2013). This could potentially be linked with the absence of MRP4 in a premature neonate with GA 24 weeks. However, these data should be confirmed as we only had 1 sample of ±24 weeks GA available. Moreover, our data help us in understanding altered disposition of transporter substrates in paediatrics.

References

Pacifici, G. M. ( 2013). Clinical pharmacology of furosemide in neonates: a review. Pharmaceuticals;6(9):1094–1129.

Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H, Grube M, Köck K, & Kroemer HK. ( 2005). Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug metabolism reviews;37(1):253–278.

Disclosure(s)

Nothing to disclose
P102 Alternative splicing of the SLCO1B1 transporter in paediatric liver
Authors: van Groen BD , Bi C , Gaedigk R , Staggs V , Tibboel D , de Wildt SN , Leeder JS
Published: May 2019

Background

Alternative mRNA transcripts occur in >90% of human genes and may be triggered by developmental signals. The hepatic transporter OATP1B1 (gene name SLCO1B1) traffics substrates across the hepatic membrane, and shows age-related changes in protein expression. We aimed to predict novel isoforms of OATP1B1 by studying alternative splicing of SLCO1B1 in human paediatric post-mortem liver tissue, and the relationship of their mRNA expression with age.

Methods mRNA expression of SLCO1B1 transcripts was determined using RNA sequencing (HISAT2/StringTie). Novel mRNA transcripts were considered of relevance when (1) the expression was >5% of the annotated isoform, (2) it was a SLCO1B7 and SCLO1B1 hybrid transcript, or (3) when the expression was associated with age. The software packages ORF-finder, TMpred and TOPO2 were used to predict the protein sequence and structure of the novel isoforms. Relationship of expression with age was studied with the Kruskal-Wallis test for age groups (fetal, 0–1.5 year, 1.5–6 year, 6–12 year and 12–18 year) and with Spearman correlation tests for age on continuous scale.

Results

In 97 hepatic post-mortem tissues (gestational age median 16.4 [range 14.7–41.3] weeks, postnatal age 0.36 [0 - 17] years) 27 novel mRNA transcripts were detected. Of these, 13 were relevant: 2 isoforms are predicted to translate into amino acid sequences similar to the annotated isoform for OATP1B1, 9 isoforms may translate into truncated versions, and the expression of 8 isoforms was associated with age. None of the isoforms had an ORF that covered the SLCO1B7 region.

Conclusion

We showed that novel SLCO1B1 mRNA isoforms potentially translate into OATP1B1 protein with unknown function, and that alternative splicing may well be a regulatory mechanism for SLCO1B1 expression during development. This data provides a better understanding of age-related changes in the expression of OATP1B1, and, with that, potentially improves prediction of disposition of endogenous and exogenous substrates.

Disclosure(s)

BG was supported, in part, by the Ter Meulen fund 2018 provided by the Royal Dutch Academy of Sciences. The National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland is funded by the National Institutes of Health (NIH) contract HHSN275200900011C, reference number, N01-HD-9-0011 and the Liver Tissue Cell Distribution System is funded by NIH contract number N01-DK-7-0004/HHSN267200700004C.
P103 Target attainment of amikacin therapy in critically ill children
Authors: Verbruggen J , Jakipbayeva K , Van Der Heggen T , Dhont E , Dhondt L , Vande Walle J , De Paepe P , Herck I , De Cock P
Published: May 2019

Background

Research regarding the optimal amikacin (AMI) dosing regimen in critically ill children is scarce.1 Optimal AMI efficacy has been observed with plasma peak over minimal inhibitory concentration of the suspected pathogen (peak/MIC) ratios of 8 to 10. Plasma trough levels (Cmin) >5mcg/ml are related to its toxicity.

The objectives of this pilot study were to: (1) evaluate target attainment rate and occurrence of supratherapeutic concentrations in early and assumed steady-state dose conditions, and (2) investigate the correlation between AMI clearance and estimated glomerular filtration (eGFR).

Methods

Children admitted to the ICU receiving intravenous AMI (20 mg/kg once daily) were included. Serial blood samples were obtained from early (1st/2nd) and assumed steady-state (SS) doses. The evaluated target peak concentration range was 54–64 mcg/ml, assuming a Pseudomonas aeruginosa infection with Eucast MIC breakpoint of 8 mg/L, and a Cmin threshold of 5 mcg/L. eGFR was estimated using the modified Schwartz formula. AMI clearance was calculated using noncompartmental PK analysis. Correlation was assessed by means of a scatter plot and Pearson Correlation Coefficient (r).

Results

Twenty-one patients (median age

1,5 years; range:0,5 months-14 year, median eGFR 162 ml/min/1,73m2 (range:107–475 ml/min/1,73m2) were included. In early dose conditions, 69% of patients had therapeutic peak concentrations (median: 60 mcg/ml; range:26–73 mcg/ml). In SS conditions, 60% of patients had therapeutic peak concentrations (median: 59 mcg/ml; range:35–83 mcg/ml). Only one supratherapeutic Cmin was observed. AMI clearance (median 0.08L/h/kg; range: 0.05–0.91 L/h/kg) was comparable to what has been previously reported but showed no correlation with eGFR (r=0.1; p=0,66) [1].

Conclusion

This pilot study suggest that the current AMI dosing regimen may lead to subtherapeutic concentrations in patients infected with less susceptible pathogens. Supratherapeutic Cmin were far less of a concern. Dose adjustments of renally cleared drugs based on eGFR may not be reliable in this patient population.

References

Illamola SM, Sherwin CM, van Hasselt JGC. Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive review of Population Pharmacokinetic Analysis. Clin Pharmacokinet ( 2018) 57:1217.

Disclosure(s)

Nothing to disclose
P110 Population pharmacokinetics and dosing optimisation of imipenem in children with haematological malignancie
Authors: Dong L , Zhai X-Y , Yang Y-L , Wang L , Zhou Y , Shi H-Y , Tang B-H , Y-E Wu , Yang F , Wen L , Kong H-X , Zhi L-J , Jacqz-Aigrain E , Zhao W
Published: May 2019

Background

Imipenem/cilastatin is widely used for the treatment of children with serious infections. Currently, there is lack of pharmacokinetic studies of imipenem in children with hematological malignancies. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population based pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population.

Methods

After treated with IMP/CS, blood samples of children were collected and the concentration of imipenem were quantified using HPLC-UV. Then, population level pharmacokinetic analysis was conducted using NONMEM software.

Results

Data from 56 children (age range: 2.03–11.82 years) with haematological malignancies were collected to conduct a population based pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be best suitable. The parameters of current weight, age and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 52.0%, 65.2% and 76.6% of children reached the pharmacodynamic target (70% fT>MIC) against sensitive pathogens with an MIC of 0.5 mg/L at 15, 20 and 25 mg/kg q6h of imipenem, respectively. However, only 17.2% of children achieved the pharmacodynamic target against Pseudomonas aeruginosa with an MIC of 2 mg/L at a dose of 25 mg/kg q6h.

Conclusion

Population pharmacokinetics of imipenem was assessed in children. The current dosage regimens of imipenem are underdose for resistant pathogens including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h.

Disclosure(s)

Nothing to disclose.
O15 Lidocaine plasma concentrations and anti-epileptic efficacy in term and preterm neonates: prospective validation of a new dosing regimen
Authors: Favié L , Rademaker C , van den Broek M , Egberts T , van Bel F , Groenendaal F
Published: May 2019

Background

Lidocaine is used as an add-on anti-epileptic drug (AED) in neonates when seizures persist despite treatment with first line anticonvulsants. Although lidocaine has shown to be an effective anticonvulsant, cardiac toxicity associated with plasma concentrations >9 mg/L have limited its wide scale use.1 Previous studies from our group have proposed a dosing regimen for effective and safe lidocaine use in term and preterm neonates with plasma concentrations not exceeding 9 mg/L.2,3

Aim

The present study evaluated lidocaine use as anticonvulsant in neonates and prospectively validated the new dosing regimen.

Methods

Data were collected at the neonatal intensive care unit of the University Medical Centre Utrecht. Neonates refractory to at least one AED received lidocaine according to clinical protocol. Lidocaine was administered as a 2 mg/kg loading dose in 10 minutes followed by a three stage maintenance phase with tapering lidocaine doses. Lidocaine plasma concentrations were measured from blood samples taken at the end of the first stage (highest lidocaine dose) and during the second or third stage (tapered lidocaine dose). Efficacy was determined as abolishment of seizures during lidocaine therapy and no recurrence within 24 h after cessation.

Results

Lidocaine data were available from 75 neonates (gestational age 36.2 weeks [range 25.0–42.4, < 36.0 38.7%], birth weight 2771 g [range 675–4875], male 64.0%, mortality 45.3%). 23 patients (30.7%) received the new dosing regimen, 52 patients (60.7%) the old regimen. Highest measured plasma concentration with the new regimen was 9.15 mg/L and 16.8 mg/L with the old regimen. Efficacy with the new regimen was 56.5% and 53.8% for the old regimen. No cardiac toxicity was observed in either group.

Conclusions

The new lidocaine dosing regimen leads to safe and effective lidocaine plasma concentrations and has similar efficacy compared to the previous dosing regimen.

References

Weeke LC, Toet MC, Van Rooij LGM, Groenendaal F, Boylan GB, Pressler RM, et al. Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants 2015;233–42.

Van den Broek MPH, Rademaker CMA, van Straaten HLM, Huitema ADR, Toet MC, de Vries LS, et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed 2013;98(4):F341–5.

Van Den Broek MPH, Huitema a. DR, Van Hasselt JGC, Groenendaal F, Toet MC, Egberts TCG, et al. Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. Clin Pharmacokinet 2011;50(7):461–9.

Disclosure(s)

Nothing to disclose
P113 Population pharmacokinetics and dosing optimization of azlocillin in neonates
Authors: Zhao W , Group TINN-Global Study
Published: May 2019

Background

Azlocillin is prescribed for the treatment of infections in neonatal clinical practice, however, the optimized dose is still questionable due to the lack of pharmacokinetic study Thus, we aim to evaluate the population pharmacokinetics of azlocillin and optimize dosing regimen in order to improve azlocillin treatment in neonates.

Methods

This is a prospective, open label pharmacokinetic study of azlocillin. Blood samples were collected using an opportunistic sampling design. Theplasma concentrations ofazlocillinwere determined by high performance liquid chromatography method with UV detection. Population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM software.

Results

Ninety-five neonates (postmenstrual age (PMA) range 32.1–42.0 weeks) were included in this study. A total of 167 azlocillin concentrations were available for the final analysis. A one-compartment model with first-order elimination best fitted the data. Covariate analysis demonstrated that current weight, birth weight and postnatal age had significant effect on azlocillin pharmacokinetics. MonteCarlo simulation demonstrated that for the common pathogens with MIC of 8 mg/liter, the currently used dosage regimen (100 mg/kg, q12h) resulted in 61.2% of newborns achieved the pharmacodynamic target (drug concentrations above MIC during 70% of the dosing interval) with a potential risk of underdosing. When shortening the dosing interval to 8 hours, the target could be achieved in 89.3% of patients, using the MIC break point of 8 mg/liter.

Conclusion

The population pharmacokinetics characteristics of azlocillin were assessed in neonates. An optimal dosage regimen of azlocillin was established based on developmental pharmacokinetics-pharmacodynamics in this vulnerable population.

Disclosure(s)

Nothing to disclose.
P115 Effects of the clinical pharmacist’s intervention on rationality of parenteral nutrition
Authors: Zhu M , Xu J
Published: May 2019

Objective

Through STRONGkids1 2 (screening tool risk on nutritional status and growth of children) to observe the influences on nutritional indicators and postoperative recovery of different nutritional risk levels of children with intussusception in the use of parenteral nutrition support. Through educating and interventing the doctors to promote the use of parenteral nutrition more reasonable and the hospitalization costs lower.3

Methods

Children were grouped according to different scores of STRONGkids,4 5 and each group was divided into two groups A and B according to using parenteral nutrition only or no nutrition support at all. The proportion of the two groups, nutritional indicators and postoperative recovery of the children after surgery were compared to observe the parenteral nutrition usage rate of different groups, and the use of parenteral nutrition was necessary or not. The clinical pharmacist intervened the doctors according to the research results. 1 year later, the indicators above were compared again.

Results

There were no significant differences on nutritional indicators and postoperative recovery in 1–2 score groups between group A and B, but the hospitalization cost in group A was significantly higher than that in group B. In 3-score group of children, the decreases of weight, prealbumin and retinol binding protein were more significant in group B than in group A, and the hospitalization days of group A were significantly shorter than group B. The incidence of adverse reactions of using parenteral nutrition was significantly higher. According to above results, the clinical pharmacist instructed doctors to improve the indication of parenteral nutrition according to the relevant guidelines.1 year later, the usage rate of parenteral nutrition dropped in 1–2 score groups. The incidence of adverse reactions and the costs of hospitalization were significantly decreased.

Conclusions

The clinical pharmacist played an important role in promoting the rational use of parenteral nutrition.6 7

References

Teixeira AF, Viana KD.Nutritional screening in hospitalized pediatric patients: a systematic review.[J]J Pediatr (Rio J) 2016, 92(4):343–352.

Forga L, Bolado F, Goñi MJ,et al. Low serum levels of prealbumin, retinol binding protein, and retinol are frequent in adult type 1 diabetic patients.J Diabetes Res2016; 2016:2532108. doi: 10.1155/2016/2532108. Epub 2016 Nov 29.

Pediatric Collaborative Group, Society of Parenteraland Enteral Nutrition. Guidelines for pediatric clinical application of enteral and parenteral nutritional support in China[J]. Zhonghua Er Ke Za Zhi, 2010, 48(6):436–441.

Abunnaja S, Cuviello A, Sanchez JA.Enteralandparenteral nutritionin the perioperative period: state of the art[J].Nutrients. 2013, 5(2):608–623.

Yi F, Ge L, Zhao J, Lei Y,et al.Meta-analysis:total parenteral nutritionversustotalenteral nutritionin predicted severe acute pancreatitis[J].Intern Med. 2012, 51(6):523–530.

Disclosure(s)

Nothing to disclose.
O16 Piglets as animal model to assess the contribution of fluid therapy to the development of augmented renal clearance in children
Authors: Dhondt L , Croubels S , De Paepe P , De Cock P , Devreese M
Published: May 2019

Background

The past years augmented renal clearance (ARC), observed in the critically ill paediatric population, has received an increased attention by researchers due to its major impact on drug exposure.1 Since a recent report demonstrated that the maturation of the glomerular filtration rate (GFR) in juvenile pigs is comparable to children, pigs may be a potential animal model to investigate the impact and mechanisms of ARC on drug pharmacokinetics (PK) in children.2

In this pilot study, the contribution of intravenous (IV) fluid administration on the development of ARC was investigated in piglets.

Methods

Eight seven-week-old pigs underwent an experiment without fluid therapy and two consecutive fluid treatments as CRI of a 0.9% NaCl solution (3 mL/kg/h and 6 mL/kg/h) over 36 hours, each time combined with IV administration of a cocktail of renal markers after 4 and 24 h of fluid administration. This cocktail consisted of iohexol (64.7 mg/kg body weight (BW), Omnipaque 300®, marker for GFR) and para-aminohippuric acid (10 mg/kg BW, marker for effective renal plasma flow). To assess the impact of ARC on the PK of antimicrobials, amikacin (7,5 mg/kg BW, Amukin®) was administered after 24 h of fluid therapy. PK modelling was performed with Phoenix® WinNonlin®.

Results

Generally, an increase in GFR was observed after fluid administration when compared to the GFR values observed without fluid administration. 4 and 2 out of 7 pigs demonstrated ARC after 4 h of a CRI at 3 mL/kg/h and 6 mL/kg/h, respectively. 4 out of 7 pigs displayed ARC after 24 h of a CRI at 3 mL/kg/h and 6 mL/kg/h. Similar results were obtained for amikacin clearance.

Conclusion

An important effect of fluid therapy on the development of ARC was observed in juvenile pigs. Further research is necessary to confirm this results in critically ill children.

References

Dhont E, et al. Augmented renal clearance in pediatric intensive care: are we undertreating our sickest patients? Pediatric Nephrology 2018.

Gasthuys E, et al. Postnatal Maturation of the Glomerular Filtration Rate in Conventional Growing Piglets As Potential Juvenile Animal Model for Preclinical Pharmaceutical Research. Frontiers in Pharmacology 2017;8.

Disclosure(s)

This study was funded by the Special Research Fund of Ghent University (BOF16/DOC/285).
O19 Development of a paediatric brain PBPK model in children with and without meningitis
Authors: Verscheijden LFM , Koenderink JB , Allegaert K , de Wildt SN , Russel FGM
Published: May 2019

Background

Several paediatric physiologically-based pharmacokinetic (PBPK) models have been developed that incorporate developmental changes affecting plasma drug concentrations. Disposition into cerebrospinal fluid (CSF) is also age-related and influenced by physiological factors, including CSF production rate, but also by brain diseases, such as meningitis, which are associated with impaired blood-brain barrier integrity. Our aim was to develop a paediatric brain PBPK model to predict CSF drug concentrations in children with and without meningitis.

Methods

A paediatric PBPK model was developed incorporating age-appropriate parameters and associated inter-individual variability. The model was validated for paracetamol, ibuprofen, flurbiprofen and naproxen, and for a paediatric meningitis population by estimating meropenem blood-brain barrier penetration using sensitivity analysis. Plasma and CSF drug concentrations derived from literature were used to perform visual predictive checks and to calculate ratios between simulated and observed AUCs in order to evaluate model performance.

Results

Simulated data were comparable to observed over a broad age range (1 day - 15 y postnatal age), for all drugs investigated. The ratios between observed and simulated AUCs were within 2-fold difference both in plasma and in CSF, indicating acceptable model performance. Disposition of meropenem into the brain was slow and CSF concentrations were lower compared to plasma concentrations. In addition, several days were needed to achieve CSF steady-state concentration.

Conclusions

Our paediatric brain PBPK model provides a new tool to predict CSF concentrations in children with and without meningitis and can be used as a template model for other drugs acting in the CNS.

Disclosure(s)

Nothing to disclose
O20 Dose-linearity of the pharmacokinetics of an intravenous [14C]midazolam microdose in children
Authors: van Groen BD , Vaes WHJ , Park BK , Krekels EHJ , van Duijn E , Kõrgvee L-T , Maruszak W , Grynkiewicz G , Garner RC , Knibbe C , Tibboel D , de Wildt SN , Turner MA
Published: May 2019

Background

Drug disposition in children may vary from adults due to age-related variation in drug metabolism, but paediatric pharmacokinetic (PK) studies are challenging. Microdose studies present an innovation to study PK in paediatrics, and can only be used when the PK of a microdose are dose-linear to a therapeutic dose. We aimed to assess dose-linearity of [14C]midazolam (MDZ), a marker for the activity of the developmentally regulated CYP3A enzyme, by comparing the PK of an intravenous (IV) [14C]MDZ microtracer given simultaneously with therapeutic MDZ, with the PK of a single IV [14C]MDZ microdose.

Methods

Preterm to 2-year-old infants admitted to the intensive care unit received [14C]MDZ IV either as a microtracer during therapeutic MDZ infusion or as an isolated microdose. Dense blood sampling was done up to 36 hours after dosing. Plasma concentrations of [14C]MDZ and [14C]1-OH-MDZ were determined by accelerator mass spectrometry. A population PK model was developed with NONMEM 7.4 to study whether there was a difference in the PK of the microtracer versus those of a microdose [14C]MDZ.

Results

Of fifteen children (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), nine received a microdose and six a microtracer [14C]MDZ (111 Bq/kg; 37.6 ng/kg). In a two-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the [14C]MDZ microdose or microtracer, suggesting the PK of MDZ to be linear within the range of the therapeutic doses and microdoses.

Conclusion

Our data supports the dose-linearity of an IV [14C]MDZ microdose in children, thus a [14C]MDZ microdosing approach can be used to study developmental changes in hepatic CYP3A activity.

Disclosure(s)

This project was funded by the ZonMw ERA-NET PRIOMEDCHILD programme (projectnumber 113205022). * both authors contributed equally
O24 Ivermectin in children: what is the right dose to achieve equivalent exposure coverage in children and adults?
Authors: Brussee JM , Schulz JD , Coulibaly JT , Keiser J , Pfister M
Published: May 2019

Background

The broad-spectrum antiparasitic drug ivermectin is widely used in children, and its use in children weighing < 15 kg is off-label, as little data is available to inform the use of ivermectin in this young age group. Pediatric doses associated with consistent exposure across age are still unknown. Therefore, we aim to identify a dosing strategy for ivermectin treatment in both pre-school-aged children (2–5 years of age) and school-aged children (6–12 years of age) that achieves equivalent exposure coverage in children and adults.

Methods

A population pharmacokinetic model for ivermectin was developed based on data collected in 80 pre-school-aged children (2–5 years), 120 school-aged children (6–12 years),1 and eleven adults,2 receiving an oral dose of 100–600 µg/kg ivermectin. Model-based simulations were performed to optimize pediatric dosing to achieve consistent exposure across various age groups.

Results

Clearance per kilogram was higher in children than in adults, with a median (90% confidence interval) of 0.35 (0.12–0.73) L/h/kg in children compared to 0.20 (0.10–0.31) L/h/kg in adults. As a result, ivermectin exposure in children following a 200 µg/kg dose is ∼30% lower than in adults. An increased dose of 250 and 300 µg/kg would be needed in school-aged children (6–12 years) and pre-school-aged children (2–5 years), respectively, to achieve equivalent exposure coverage in children and adults. Alternatively, we propose a height-based dosing schedule with a stepwise increase in number of administered 3-mg-tablets from 1 to 5 for children in sub-Saharan Africa with a height of 75–90 cm, 90–130 cm, 130–150 cm, 150–165 cm, and 165–175 cm.

Conclusion

We report the first dosing strategy for the widely-used drug ivermectin that is associated with equivalent exposure coverage in children and adults. Further studies are necessary to establish the safety and efficacy of appropriate doses in the pediatric population.

References

Wimmersberger D, Coulibaly JT, Schulz JD, Puchkow M, Huwyler J, N´Gbesso Y, et al. Efficacy and Safety of Ivermectin Against Trichuris trichiura in Preschool-aged and School-aged Children: A Randomized Controlled Dose-finding Trial. Clin Infect Dis 2018; 67(8):1247–55.

Schulz JD, Neodo A, Coulibaly JT, Keiser J. Development and validation of a LC-MS/MS method for ivermectin quantification in dried blood spots: application to a pharmacokinetic study in Trichuris trichiura-infected adults. Anal. Methods, 2018, 10, 2901–9.

Disclosure(s)

JMB declares no potential conflicts of interest. JDS declares no potential conflicts of interest. JTC declares no potential conflicts of interest. JK was financially supported by the Bill and Melinda Gates Foundation (OPP1153928) and an ERC grant (CoG 614739 A-HERO), and declares no other potential conflicts of interest. MP has a part-time employment with the consulting company Certara LP (USA), and declares no other potential conflicts of interest.
P04 Non-compartmental analysis of vancomycin pharmacokinetics in critically ill children
Authors: Akunne O , Mugabo P , Argent A
Published: May 2019

Background

Vancomycin is often used as the drug of choice in the treatment of bacteria that are methicillin resistant or in patients sensitive to penicillin. This study describes the pharmacokinetics of vancomycin in critically ill children.

Methods

Children aged 1month to 16 years admitted to the paediatric intensive care unit of the Red Cross War Memorial Hospital and on vancomycin treatment for ≥24 hours and ≤72 hours were prospectively recruited. Blood samples were collected around predetermined optimal sampling times. A minimum of three samples per patients was analysed. Non-compartmental analysis was used to determine the volume of distribution (V), clearance (CL), half-life (t1/2), area under the concentration-time curve (AUC), elimination constant (Ke) and Mean residence time (MRT). The minimum concentration (Cmin) and maximum concentration (Cmax) of vancomycin were measured directly as trough and peak plasma concentration respectively. Analysis of data was performed using PKNCA version 0.8.5 in R.

Results

Forty-nine serum concentrations from 10 patients were included in the analysis. The ratio of male to female was 1:1. Median age (Range) was 1.6 (0.2–15) years, weight = 10.6 (3.1–31.3) kg, baseline serum creatinine (Scr) = 0.31 (0.15–0.78) mg/dL. Patients received daily vancomycin doses ranging from 56 to 78 mg/kg. Mean PK parameters (range) were as follows: CL = 0.12±0.15 (0.018–0.52) L/h/kg, V =0.68±0.47 (0.15–1.57) L/kg, Ke = 0.147±0.073 (0.07–0.33) h-1, t1/2 =5.54±2.03 (2.11–9.62) h, MRT=8.02±2.92 (3.04–13.88) h, AUC =322.07±245.65 (31.6–850.4) mg/L.h, Cmin =6.21±3.66 (2.0–14.5) mg, Cmax =38.91±31.92 (10.4–97.2) mg. Trough concentration and AUC were not met in >80% and >75% of the patients.

Conclusion

Variability in vancomycin pharmacokinetics was observed in patients. At current doses, target trough concentrations and AUC were not met.

Disclosure(s)

Nothing to disclose
P05 Establishing the integrity of the continually paediatric pharmacokinetic bioanalysis for clinical trial within an academia environment using quality assessment process
Authors: Ali M , Tins J , Burckhardt BB
Published: May 2019

Background

European Medicines Agency (EMA) outlines criterion for validation of bioanalytical assay applied under Good Clinical Laboratory Practice (GCLP) within clinical studies. The validation is performed once and does not inevitably ensures comparable reliability over long duration of assay’s applicability. To address this hurdle, the investigator-driven ‘Labelling of Enalapril from Neonates up to Adolescents’ project (LENA) adapted quality system comparable to industry. A comprehensive set of quality measures was applied to ensure reliability of monthly quantified paediatric samples over duration of 31 months.

Methods

A 3-step quality approach analysing the calibration standards (CS), quality controls (QCs) and incurred sample reanalysis (ISR) was used to established reliability of unknown samples. Unknown concentrations were reported only if results of known CS (11 levels) and QCs were within the predefined limits. A maximum deviation of ±15% was acceptable at all five QCs level. ISR was conducted for randomly selected paediatric samples to monitor the assay’s performance over time. The acceptable%difference was ±20% for at least 67% of the ISR according to international guidelines. 1,2

Results

38 analytical runs were conducted for two drugs (enalapril/enalaprilat) from February 2016 to August 2018. Calibration curve evaluation accounted for exclusion of four enalapril and five enalaprilat runs. Additional investigation of QCs resulted in further exclusion of two enalapril and one enalaprilat runs. Within 32 valid runs 820, QCs were measured for enalapril and enalaprilat. 94% enalapril and 89% enalaprilat QCs were within limits (±15%). This set ensured reliable determination of 1262 LENA paediatric study samples. 93 and 104 incurred samples for enalapril and enalaprilat were reanalysed. ISR for enalapril (70%) and enalaprilat (67%) was also within guidelines.1,2

Conclusion

The analysis of bioanalytical data ensured the reliability of reported unknown concentrations. It ensured consistent and reliable pharmacokinetic data from first to the last LENA study patient.

References

Guideline on bioanalytical method validation. European Medicines Agency, London, UK ( 2011).

Guidance for Industry Bioanalytical Method Validation. US Department of Health and Human Services, US FDA, Rockville, MD, USA ( 2018).

Disclosure(s)

Mohsin Ali, Jutta Tins, Bjoern B Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)
P16 Towards determination of endogenous prorenin in paediatric samples using a hybrid approach – impact of antibody selection for immunocapture
Authors: Burdman I , Burckhardt BB
Published: May 2019

Background

Since sample volume is limited in children, innovative bioanalytical methods and enrichment procedures are highly required. The analysis of endogenous substances by liquid chromatography coupled to mass spectrometry is a highly specific method because of its selectivity and accuracy. However reliable detection of endogenous substances can only be achieved by a hybrid assay approach combining immunocapture and mass spectrometry. Key element of the immunocapture procedure is the selection of the appropriate antibody for capturing the desired antigen. This study is meant to identify the most suitable antibody that facilitates the development of an hybrid assay approach concerning reliable detection of endogenous prorenin in paediatric samples.

Methods

Dynabeads magnetic beads were coupled to three different antibodies from three different vendors (GeneTex, Molecular Innovations, R&D systems). 500 µL human plasma which was spiked with 20 ng recombinant human prorenin (Cayman chemicals). The immunocapture step was followed by protease digestion and a custom-made µelution solid-phase extraction protocol. The digest was analyzed by Shimadzu Nexera LC-system coupled with Sciex TripleTOF 6600 mass spectrometer.

Results

The analysis of the captured prorenin was performed by the surrogate peptide approach. In this case the surrogate peptide was identified as unique. The comparison of the three available antibodies showed that one antibody did not ensure reliable binding properties in human matrix. Among the two remaining antibodies only one showed sufficient binding capacities to be applied in small sample volumes commonly available in paediatric samples. Using this hybrid approach enabled the enrichment of the required volume by factor of 20.

Conclusion

This study identified the most suitable antibody for the immunocapture procedure of the prorenin hybrid approach. This is now followed by further mass spectrometric method development and validation prior to its application in paediatric samples.

Disclosure(s)

Declaration of interest: none Ilja Burdman and Bjoern B. Burckhardt declare that there is no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors