bluuebunny/crossref_metadata_2025_split huggingface dataset:
P88 The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients
Authors: Schijvens A , van Hesteren F , Cornelissen M , Bootsma-Robroeks C , Brüggemann R , Burger D , de Wildt S , Schreuder M , ter Heine R 
Published: May 2019

BackgroundTacrolimus is an important immunosuppressive agent with high intra- and interindividual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration, is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients.MethodsData were obtained from 36 pediatric kidney transplant patients. 255 tacrolimus whole blood samples were available, together responsible for 36 area under the concentration time curves (AUCs) and trough concentrations. First, hematocrit-corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated.ResultsIn total, 92% of our patients had a lower hematocrit (median 0.29) than the reference value of adult renal transplant patients. A different evaluation of target exposure for either trough level, AUC or both, was defined in 42% of our patients, when applying hematocrit corrected concentrations.ConclusionA critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.Disclosure(s)All authors declare that they have no conflict of interest. This work was recently accepted for publication in Pediatric Nephrology. We are aware of the statement in the guideline about previously published work, however as we believe that this work suits the aim and topics of the congress very well, we chose to submit this work and will ofcourse leave the final decision to you.
O13 Improved early vancomycin exposure in neonates using a population pharmacokinetic model-based vancomycin dosing regimen
Authors: Smits A , De Saeger E , Vandendriessche A , Cossey V , Allegaert K 
Published: May 2019

BackgroundWe previously documented that 2 published vancomycin dosing regimens resulted in subtherapeutic exposure in 66.3 and 76.2% of neonates.1 A new dosing regimen derived from a population pharmacokinetic (PK) analysis and using a loading dose, was implemented in our unit.2 We aimed to investigate if the new regimen results in improved vancomycin exposure (target trough 10–15 mg/L).MethodsClinical data and early (24 h after start) vancomycin therapeutic drug monitoring (TDM) in neonates receiving vancomycin for medical reasons, were retrospectively collected and pooled with 2 historical cohorts [cohort 1 (2011, n=193 observations), dosing based on postmenstrual age (PMA) and creatininemia and cohort 2 (2012, n=101 observations), dosing based on PMA and postnatal age (PNA)]. The new regimen [cohort 3 (2018, n=71 observations)] consists of a loading dose, followed by dosing based on birthweight, PNA and ibuprofen co-treatment [2]. Clinical characteristics and early TDM were compared across the cohorts using the Kruskal-Wallis Test. Results were significant if p< 0.05.ResultsClinical characteristics (cohort 1, 2 and 3 respectively) did not differ significantly across the cohorts. Median (IQ range) GA was 32.8 (28.4–37.6), 32.1 (28.5–37.5), 28 (26–38) weeks with p=0.097; PNA 13 (6–26), 12 (7–23), 14 (10–25) days with p=0.15 and creatininemia 0.43 (0.33–0.55), 0.49 (0.33–0.65), 0.45 (0.32–0.57) mg/dL with p=0.15. Median vancomycin trough level was 7.8 (5.1–11.3), 5.8 (4.1–8.7), 13.3 (9.9–17.3) mg/L with p< 0.0001. With the new regimen, 25.4% of trough levels was < 10 mg/L, 40.8% >15 mg/L, and 33.8% was on target, versus 23.3 and 19.8% on target in cohort 1 and 2 respectively.ConclusionA population PK model-based vancomycin dosing regimen using a loading dose, resulted in improved neonatal vancomycin exposure. Although only 25% of trough levels was subtherapeutic, dosing optimalisation for cases with supratherapeutic exposure is also needed, as well as further prospective validation.ReferencesVandendriessche, et al. Curr Ther Res Clin Exp 2014.Janssen, et al. AAC 2015.Disclosure(s)Nothing to disclose
P95 Compilation of available plasma renin activity levels in the healthy and cardiac diseased paediatric population
Authors: Suessenbach FK , Gangnus T , Burdman I , Makowski N , Laeer S , Burckhardt BB 
Published: May 2019

BackgroundThe physiological and pathophysiological characteristics regarding plasma renin activity (PRA) in the context of the renin-angiotensin-aldosterone-system (RAAS) are well investigated in adults, whereas less is known in paediatric population suffering from heart failure. Challenges in the conduct of paediatric investigations limit the enrolled children often to specific age groups allowing only a partial revaluation of the maturating RAAS. To constitute the comprehensive picture of the paediatric RAAS from 0–18 years, a compilation of available PRA data was conducted via literature search.MethodsA systematic literature search was accomplished in the context of the ‘Labeling of Enalapril from Neonates up to Adolescence’ (LENA) project in the MEDLINE database via PubMed in January 2019. Key words: plasma renin activity and congenital heart disease/dilative cardiomyopathy/heart failure/congenital heart defect and child/neonate/infant/toddler/paediatric. Eligible records included PRA values in children of 0–18 years of age. Exclusion criteria comprised foetuses, preterm, cord blood, urine, adults, < 2500 g birthweight, ex vivo studies and deviant diseases.ResultsLiterature search resulted in 167 findings of which 58 full-text articles were assessed for eligibility. Finally, 33 publications were classified as relevant. Of these, 21 and 12 records were assigned for healthy and cardiac diseased population respectively, leading to PRA data sets of 2000 healthy and 254 diseased children. Visual check of data revealed an age dependent decrease of PRA, in particular in the early childhood, and a substantial elevation of PRA in heart failure patients.ConclusionThe conducted literature search allowed a systematic description of PRA values in healthy and cardiac diseased paediatrics, which facilitates a classification of reference ranges of the maturing RAAS for LENA and future paediatric trials.Disclosure(s)Fabian K. Suessenbach, Tanja Gangnus, Ilja Burdman, Nina Makowski, Stephanie Laeer 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).
P97 Busulfan/sulfolane metabolic ratio on the third day of conditioning may predict the event-free survival in children receiving busulfan based conditioning prior to hematopoietic stem-cell transplantation
Authors: Uppugunduri CRS , Rezgui MA , Huezo-Diaz CP , Nava T , Mlakar S , Théoret Y , Bittencourt H , Krajinovic M , Ansari M 
Published: May 2019

BackgroundBusulfan (Bu) is widely used as a component of myeloablative conditioning regimen before hematopoietic stem cell transplantation (HSCT) in children. Obtaining the ratio of Bu to its metabolite sulfolane i.e. metabolic ratio (MR) may serve as an indicator of Bu GSH conjugating capacity of an individual.ObjectiveTo evaluate the utility of Bu MR to predict EFS in children undergoing allogeneic HSCT.MethodsTwo different cohorts with children receiving Bu in four times daily (QID, n=44) and once daily doses (QD, n=13) at St. Justine’s Hospital, Montreal were studied. Bu and Su levels were measured on day 3 of the conditioning regimen at the end of infusion (dose 9 in QID or dose 3 in QD dosing). EFS was defined from the time of transplant until death, relapse, or rejection, whichever occurred first. A receiver-operator characteristic curve (ROC) of Bu MRs was analyzed in relation to EFS. Cutoff values were defined based on the Youden´s J statistic.ResultsTwenty-two males and 22 females aged from 0.1 to 19.9 years (mean±SD: 7.2 ± 5.7) from Bu QID cohort had the mean MR of 5.9 (SD: 3.2). A cut off value of 4.9 in MR was chosen in ROC analysis in this cohort, with better sensitivity (71%) and specificity (70%) for EFS prediction (p=0.01, AUC= 0.7 (95% CI= 0.6–0.8). In QD cohort nine females, and four males aged between 0.4 and 15.8 years (6.7±5.1) had the mean MR of 29.3 (SD: 16.6). In ROC analysis, a cut off value of 25.06 was chosen with better sensitivity (100%) and specificity (100%) for EFS prediction (p=0.003; AUC=1.0).ConclusionThe Bu MR on day 3 above 4.973 and 25.06 were associated with worse EFS in children undergoing HSCT and received Bu in QID and QD dosing schedules, respectively.Disclosure(s)Nothing to disclose
P107 How significant is the lack of formulations for paediatric inpatients?
Authors: Zahn J , Rascher W , Neubert A 
Published: May 2019

BackgroundPharmacotherapy in children is complex requiring individual dosages of an active substance which are often not compatible with commercially available medicinal products.1–2 Manipulations of medicinal products, e.g. splitting or mortaring of tablets are common practice and often unavoidable although they entail risks for the patient as they can affect dosing accuracy, bioavailability and integrity of the dosage form.3–4In this study we aim to determine how many medicines have to be manipulated before administration in a hospital setting in Germany.MethodsA prospective observational approach was used to determine all manipulations of drugs orally administered on two wards of a German children´s hospital. A pharmacist systematically observed the nurses and documented all steps of the medication preparation processes for 7 days. Data was analysed using descriptive analysis. Types of manipulations were evaluated on the basis of the relevant summary of product characteristics (SmPC).ResultsDuring the pilot phase 170 medication preparation processes were monitored. In 36,5% (n=62) of the observed processes medicines had to be manipulated. 54,3% (n=19) of the patients were affected by at least one manipulation. 48,4% (n=30) of all manipulations were unauthorized by the relevant SmPC affecting 37,1% of the patients. In 60,0% the reason for unauthorized manipulation was unsuitable strength of the available formulation. Dosage forms affected by unauthorized manipulations were tablets (n=28) and granules (n=2). Active substances most frequently involved in unauthorized manipulations were Omeprazole (n=11), Phenobarbital (n=7) and Topiramat (n=3).ConclusionOverall, these results reveal that manipulations to medicines prior to administration are frequent on paediatric wards in Germany. About half of the manipulations are unauthorized indicating that no suitable paediatric formulation is available. Further investigation is needed to determine the preventability and the risks associated with the overall aim of improving safety of drug therapy in children.ReferencesSchirm E, Tobi H, de Vries TW, Choonara I, De Jong-van den Berg LT. Lack of appropriate formulations of medicines for children in the community. Acta paediatrica(Oslo, Norway:1992) 2003;92(12):1486–9.Richey RH, Craig JV, Shah UU, Nunn AJ, Turner MA, Barker CE, et al. MODRIC - Manipulation of drugs in children. International journal of pharmaceutics. 2013;457(1):339–41.Bjerknes K, Boyum S, Kristensen S, Brustugun J, Wang S. Manipulating tablets and capsules given to hospitalised children in Norway is common practice. Acta paediatrica(Oslo, Norway: 1992) 2017;106(3):503–8.Paparella S. Identified safety risks with splitting and crushing oral medications. Journal of emergency nursing: JEN: official publication of the Emergency Department Nurses Association 2010;36(2):156–8.Disclosure(s)Nothing to disclose
P108 Pharmacokinetics of mycophenolic acid for systemic lupus erythematosus in children
Authors: Zhang D , Elie V , Magreault S , Melki I , Baudouin V , Jacqz-Aigrain E 
Published: May 2019

BackgroundMycophenolate mofetil (MMF) is increasingly used in children with systemic lupus erythematosus (SLE). Monitoring of its active metabolite, mycophenolic acid (MPA), is performed for individual dosage adjustment of MMF and is based on determination of area under the plasma concentration-time curve (AUC12h) of MPA. The objective of this monocentric study is to describe the pharmacokinetics (PK) of MPA in paediatric patients with SLE or lupus nephritis.MethodsPatients with lupus treated by MMF between January 2009 and July 2018 were included. MPA plasma concentrations (T0, T0.5h, T1h, T2h, T3h, T8h and T12h) were determined by EMIT (enzyme-multiplied immunotechnique) and MPA AUC12h calculated according to trapezoid rule.ResultsTwenty-two patients were diagnosed with lupus at 11.5 ± 2.9 years. Clinical presentation was SLE (n=18) or isolated lupus nephritis (n=4). Treatments prior to MMF were steroids and/or immunosuppressants (endoxan, rituximab). Age at initiation of MMF (Cellcept®n=20, Myfortic®n=2) was 12.9 ± 2.6 years.PK of MPA was performed after 8.2 ± 14.8 months of treatment, under MMF dose of 840 ± 218 mg (577 ± 98 mg/m2). A large interindividual variability in MPA concentration-time profiles was observed with the following mean parameters: Cmax=4.60 ± 11.70 µg/mL, tmax=80 ± 77 min, trough plasma concentration (C0) = 2.30 ± 1.60 µg/mL and AUC0-12h=46.29 ± 17.39 µg*h/mL.ConclusionData on the PK of MPA in lupus children are limited. Our results show the high interindividual variability in MPA exposure after oral administration of MMF. Monitoring of exposure based on AUC in combination with immunological disease parameters will allow to individualise treatment to optimiseDisclosure(s)Nothing to disclose
P109 Optimal dosing regimen of caspofungin in children: milligram per kilogram or milligram per square meter?
Authors: Yang X-M , Leroux S , Storme T , Zhang D-L , Adam de Beaumais T , Shi H-Y , Yang Y-L , Wang X-L , Zhao W , Jacqz-Aigrain E 
Published: May 2019

BackgroundCaspofungin is the first echinocandin to be used as a first-line antifungal agent for Candida spp. infections in febrile, neutropenic adult and paediatric patients. To date, the optimal dosing of capofungin in children has not been determined. We evaluated the population pharmacokinetics of caspofungin in children (2–12 years old) and defined an appropriate dose in order to optimize caspofungin treatment in this vulnerable population.MethodsBlood samples were collected from 48 children treated with caspofungin and drug concentrations were quantified by HPLC-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM softwareResultsData from 48 children was available for population pharmacokinetic analysis. A two-compartment model with first-order elimination had the best fit with the data. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics compared to body weight. Monte Carlo simulation demonstrated that >90% of a simulated paediatric population (age range, 2–12 years) treated with a loading dose of 70 mg/m2 followed by a 50 mg/m2 maintenance dose once daily would reach a minimum inhibitory concentration of 1 µg/mL, the proposed susceptibility breakpoint for caspofungin against Candida spp.ConclusionThe population pharmacokinetics of caspofungin was evaluated and revealed that adjustment of caspofungin based on body surface area is most appropriate for paediatric use.Disclosure(s)Nothing to disclose
P116 Prophylactic use of enoxaparin during bariatric surgery in adolescents with severe obesity
Authors: Ziesenitz V , Vaughns J , Williams E , Nadler E , Mikus G , van den Anker J 
Published: May 2019

BackgroundSevere obesity predisposes adults and youth to a higher risk of venous thromboembolism (VTE). Enoxaparin is frequently used for their VTE management. This study evaluates a BMI-stratified prophylactic dosing regimen of enoxaparin in severely obese adolescents undergoing bariatric surgery.MethodsThis prospective study enrolled severely obese adolescents aged 12–20 years undergoing laparoscopic sleeve gastrectomy. Prophylactic enoxaparin was dosed at 40 mg SC (for a BMI less than 50 kg/m2) and 60 mg SC (for a BMI equal to or greater than or 50 kg/m2). Blood samples were drawn until 12 hrs post-dose. Plasma Anti-Factor Xa (Anti-FXa) activity was used as a surrogate marker for enoxaparin plasma concentration and pharmacokinetics were assessed using non-compartmental PK analysis. The primary efficacy outcome was the anti-FXa activity 4–6 hours after dosing, and the primary endpoint was the proportion of patients who reached prophylactic anti-FXa activity of 0.1–0.3 U/mL between 4–6 hours after dosing.ResultsTen female and two male obese adolescents (age range 14–19 years) had a mean body weight of 140.8 kg (93.7–174 kg) and a mean BMI of 49.9 kg/m2 (38.4–58 kg/m2). Four patients received 40 mg enoxaparin, 8 patients were dosed with 60 mg enoxaparin. No VTE or major bleeding occurred. Peak plasma anti-FXa activity (Cmax) ranged from 0.14–0.30 IU/mL (median Cmax 0.205 IU/mL). Median Tmax was 5.67 hours (range 3.78–7.52 hours). Median AUCi was 1.00 h*IU/mL (range 0.42–1.67 h*IU/mL). 10 out of 12 patients (83%) reached the primary endpoint with anti-FXa activity in the range for VTE prevention (0.1–0.3 IU/mL).ConclusionsIn this single center cohort study, the dosing scheme of 40 mg vs 60 mg enoxaparin stratified according to BMI proved to be effective in reaching prophylactic anti-FXa activity in 83% of adolescent patients. This dosing scheme is in accordance with current practice in adults.Disclosure(s)J. Vaughns and J. van den Anker are supported by the Eunice Kennedy Shriver National Institute of Child Health and Development (5T32HD087969).
P117 Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study
Authors: Ziesenitz V , Rodieux F , Atkinson A , Borter C , Bielicki J , Haschke M , Duthaler U , Bachmann F , Erb T , Gürtler N , Holland-Cunz S , van den Anker J , Gotta V , Pfister M 
Published: May 2019

BackgroundThe prodrug metamizole is frequently dosed intravenously (IV) for postoperative pain in children of all ages, despite its off-label use in infants < 1 year. We aimed to investigate the pharmacokinetics (PK) of the main metabolite of metamizole, 4-aminoantipyrine (MAA), in children aged 3–72 months following IV dosing.Methods10 mg/kg metamizole was administered IV for postoperative analgesia. PK samples were drawn at 5 predefined time points. PK of the main active metabolite MAA and three other metabolites was characterized by both non-compartmental (NCA) and population PK analysis (PPK). AUC0-inf of MAA was calculated by NCA for two age cohorts (3–23 months, 2–6 years) and compared to the 80–125% range of adult dose-adjusted reference exposure (AUCref). PPK investigated age and weight dependency of the kinetics, and dosing strategies to achieve equivalent adult exposure in children.ResultsA total of 25 children aged 5 months - 5.8 years (7.8–24.8 kg) with at least one plasma concentration sample were included in PPK, 19 children who had 5 predefined samples up to 10 h post-dose were included in NCA. AUC0-inf of MAA in children of 2–6 years was 29.8 (95%CI 23.3–38.1) mg/L*h, significantly lower than AUCref(80%-125% range: 39.2–61.2 mg/L*h). AUC0-inf of MAA in infants of 3–23 months was 42.5 (95%CI 15.7–115.4) mg/L*h, overlapping with AUCref. The large variability observed in infants could be partially explained by covariates body weight and age.ConclusionsKinetics of the main active metabolite MAA depends on age in infants and children. MAA exposure after a single IV dose of 10 mg/kg metamizole in infants < 1 year of age was higher compared to an equal dose in adults and older children. This suggests that the optimal dose for this age group to achieve equivalent exposure compared to adults is lower than currently recommended.Disclosure(s)Nothing to disclose.
O25 Clavulanate stability in child-appropriate formulations is inadequate for use in treating young children in Asia
Authors: Mack I , Sharland M , Rehm S , Rentsch K , Bielicki J 
Published: May 2019

BackgroundAmoxicillin-clavulanate (AMC) is among the most frequently used antibiotic for paediatric infections globally. AMC child-appropriate formulations are largely limited to dry powder suspensions, which have to be stored refrigerated once reconstituted due to stability limitations of clavulanate.MethodsOral Amoxicillin (AMX) and AMC formulations were identified from IQVIA-MIDAS wholesale data, and 2015 antibiotic consumption in courses/1000 child-years was estimated in Bangladesh, India, Indonesia, Pakistan, Philippines and Vietnam with an assumed average treatment of 7 days. Costs per course in US-$ standardised to 2015 were estimated from the same dataset. Nationally representative data on access to a refrigerator was extracted from the Demographic & Health Surveys Program. Degradation under different temperature conditions of two different AMC suspensions commercially available in Switzerland was tested. Average degradation (three bottles of each product) was measured during 8 days with ambient temperatures of 8°C versus 28°C.ResultsIn India and Pakistan more AMC than AMX courses were sold. In all countries AMC was at least twice and up to 10 times as expensive as AMX. Access to refrigeration was below 45%, even in countries with a high number of sold AMC courses (compared with AMX). In the evaluated co-formulated products, clavulanate showed a maximum degradation of 34% at 8°C, and 73% at 28°C after 8 days. AMX was largely stable at 8°C but 13% degraded at 28°C after 8 days.ConclusionsOral amoxicillin-clavulanate suspensions are widely used in six Asian countries classified as middle-income countries by the World Bank. In reconstituted liquid AMC formulations, neither component is satisfactorily stable at room temperature. Storage conditions for stability are likely inadequate for AMC in many households in the six Asian countries of interest.Disclosure(s)Nothing to disclose