bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

BackgroundPhysiologically-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.MethodsTo 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.ResultsOver 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.ConclusionWhile 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

AimsA 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.MethodsA 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.ResultsIn 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.conclusionsThis 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

BackgroundVamorolone 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.MethodsFor 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.ResultsThe 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.ConclusionsThis 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.ReferenceConklin 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

BackgroundCaffeine 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.MethodsThe 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.ResultsPBPK 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.ConclusionsThe 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.ReferencesGiacoia, 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

BackgroundLittle 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.MethodsThis 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.ResultsA 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.ConclusionsA 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

BackgroundClavulanic 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.MethodsAs 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.ResultsAt 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.ConclusionsOral 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.ReferencesDe 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

BackgroundFentanyl 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.MethodsPreterm 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.ResultsThe 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.ConclusionThe 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

IntroductionPolybrominated 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.ObjectiveTo evaluate the exposure of infants to PBDEsMethods343 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-MSResults and discussionOut 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.ConclusionsPBDEs 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
P57 Filling the gap for children with heart failure: the EU-funded drug development program LENA (labeling of enalapril from neonates up to adolescents)
Authors: Laeer S , Breitkreutz J , Klingmann I , Lagler F , Dalinghaus M , Bajcetic M , de Wildt S , Clark AK , Breur H , Male C , Jovanovic I , Djukic M , Mir TS , Szatmári A , Vukomanovi&cacute; V , Ablonczy L , Burckhardt BB , Cawello W , Kleine K , Obarcanin E , Spatenkova L , Swoboda V , Van der Meulen M , Wagner P , Walsh J ,   on behalf of the LENA consortium
Published: May 2019

BackgroundACE-inhibitors are first choice treatment for adult and paediatric patients with heart failure. Since there are no systematic data on pharmacokinetics and safety in the young heart failure population, the EU funded a drug development program1 to fill those gaps for the ACE-inhibitor enalapril. An age appropriate paediatric formulation was also required.MethodsA paediatric patient cohort with heart failure was recruited to fulfil the paediatric investigation plan (PIP) requirements. The PIP required a total of 85 evaluable patients from birth to less than 12 years of age with a subset cohort of 25 patients with heart failure due to dilated cardiomyopathy and a subset of 60 heart failure patients of congenital heart disease. Out of these, 54% of patients must be aged below 12 months to provide a substantial amount of young patients.ResultsThe LENA consortium recruited 102 children from birth to 12 years. Out of those, 89 patients fulfilled relevant protocol criteria and could be regarded as evaluable. Of these, 26 demonstrated heart failure due to cardiomyopathy and 63 due to congenital heart disease. Sixty five patients (73%) were below 12 months of age. Moreover, 22 patients were below 3 months of age, 26 patients from 3 months to less than 6 months and 17 patients from 6 months up to 12 months of age.ConclusionsThe LENA consortium had recruited the PDCO required number of paediatric patients for the drug development program LENA. As more than 2/3 of patients belong to the most vulnerable patient population below the age of 12 months, relevant data can be generated to fill gaps for the safe and reliable treatment with ACE-inhibitors of children with heart failure.ReferencesThe research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)Disclosure(s)Nothing to disclose
P60 Serum Creatinine is superior to Serum Cystatin C in explaining inter-individual variability of vancomycin clearance in neonates and young infants
Authors: Leroux S , Biran V , van den Anker J , Zhao W , Jacqz-Aigrain E , Pfister M 
Published: May 2019

BackgroundSerum creatinine (SCr) is used as a surrogate marker of glomerular filtration rate to guide dosing of drugs eliminated by the kidney. Serum Cystatin C (S-CysC) has been suggested as a more reliable biomarker than SCr for monitoring kidney function in adults and children. Purpose of this study was to evaluate whether S-CysC is a more useful marker for estimating vancomycin clearance in neonates and young infants.MethodsPharmacokinetic (PK), Scr and S-CysC data were collected in patients undergoing continuous intravenous vancomycin treatment in the neonatal intensive care unit of Robert Debré Hospital - Paris. A population PK analysis was performed with the software package NONMEM, utilizing vancomycin therapeutic drug monitoring samples. S-CysC and SCr were compared in terms of usefulness to explain inter-individual variability (IIV) of vancomycin clearance. Statistical criteria were used for covariate selection.ResultsA total of 58 concentrations from 47 patients (gestational age [GA] ranging from 23 to 41 weeks and postmenstrual age [PMA] ranging from 26 to 46 weeks) were modeled with an allometric one-compartment model with first-order elimination. The median (range) values for SCr and S-CysC were 41.5 (12.0 to 102.0) µmol/L and 1.38 (0.95 to 2.32) mg/L, respectively. When tested individually, SCr and S-CysC explained 26.4% and 9.8% of IIV of vancomycin clearance, respectively. PMA was superior as a covariate on clearance, over the combination of GA and postnatal age. As such, bodyweight, PMA, and SCr were retained as significant covariates on clearance in the final model.ConclusionsSerum Creatinine was found to be more useful than Serum Cystatin C to explain IIV of vancomycin clearance in this population. Further studies are needed to evaluate the utility of renal biomarkers to predict clearance and dosing of renally eliminated drugs in neonates.Disclosure(s)Nothing to disclose