bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Background

Busulfan (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.

Objective

To evaluate the utility of Bu MR to predict EFS in children undergoing allogeneic HSCT.

Methods

Two 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.

Results

Twenty-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).

Conclusion

The 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

Background

Pharmacotherapy 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.3–4

In this study we aim to determine how many medicines have to be manipulated before administration in a hospital setting in Germany.

Methods

A 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).

Results

During 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).

Conclusion

Overall, 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.

References

Schirm 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

Background

Mycophenolate 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.

Methods

Patients 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.

Results

Twenty-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.

Conclusion

Data 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 optimise

Disclosure(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

Background

Caspofungin 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.

Methods

Blood 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 software

Results

Data 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.

Conclusion

The 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

Background

Severe 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.

Methods

This 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.

Results

Ten 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).

Conclusions

In 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

Background

The 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.

Methods

10 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.

Results

A 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.

Conclusions

Kinetics 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

Background

Amoxicillin-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.

Methods

Oral 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.

Results

In 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.

Conclusions

Oral 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
O26 Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young Infants
Authors: Jacqz-Aigrain E , Leroux S , Thomson AH , Allegaert K , Capparelli EV , Biran V , Simon N , Meibohm B , Y-L Lo , Marqués R , Peris J-E , Lutsar I , Saito J , Nayamura H , van den Anker JN , Sharland M , Zhao W
Published: May 2019

Background

In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.

Methods

A ‘meta-model’ using NONMEM with 4894 concentrations from 1631 neonates was built and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming at reaching a target AUC0-24 of 400 mg*h/L at steady state in at least 80% of neonates.

Results

A two-compartment model best fitted the data. Current weight, post-menstrual age (PMA) and serum creatinine were the significant covariates for clearance (CL). After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg twice daily if < 35 weeks PMA and 15 mg/kg three times daily if ≥ 35 weeks PMA) achieved the AUC0-24 target earlier than a standard ‘Blue Book’ dosage regimen in more than 89% of the treated patients.

Conclusions

The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and assist in the design of the model-based, multinational European trial, NeoVanc.

Disclosure(s)

Nothing to disclose
O27 Prospective evaluation of a population pharmacokinetic model of pantoprazole for obese children
Authors: Chapron A , Abdel-Rahman S , Shakhnovich V
Published: May 2019

Background

Pharmacokinetic (PK) data for proton pump inhibitors, acid suppressive medications commonly prescribed to children, are lacking for obese children who are at greatest risk for acid related disease. Our aim was to evaluate the performance of the only published population PK model of pantoprazole for obese children, in an independent cohort of obese and non-obese children.

Methods

A published 2-compartment structural model,1 modified to exclude transit compartments for delayed absorption, was used to predict the PK of pantoprazole (PAN) oral suspension, immediate release (ka=7.3 hr-1). Calculated population parameters and covariate relationships (e.g., weight, CYP2C19 genotype) were extracted. Predictions were based on dose, sampling times, and covariates from 57 children (6–17 years; 21% obese, 28% overweight) who received a single dose PAN and had plasma PAN concentrations collected at 10 time-points over 8 hours. Model predictive performance was assessed visually and by relative root mean squared error (RMSE), with mean ratio of predicted-to-observed area under the concentration time curve (AUC) compared via one-way ANOVA across weight groups, defined by body mass index for age (10–84th percentile normal-weight, 85–94th percentile overweight, >95th percentile obese; α=0.05, R).

Results

The model generally over-predicted observed PAN concentrations (RMSE 194%). Ratios of predicted versus observed AUC were not significantly different among obese, overweight and normal-weight children (1.5 vs. 1.7 vs. 2.2, p=0.06); however, a trend toward better model prediction was observed in the subset of obese children.

Conclusion

Observed PAN PK deviated from model predictions, which may be due to differences in patient demographics or PAN formulation. A validation study using a delayed release PAN formulation is in progress, with the overarching goal of understanding PAN disposition, and appropriate dose selection, for obese children, who are at potential risk for drug over- or under-dosing using commonly employed dosing strategies in pediatrics (e.g., mg/kg, weight-tiered).

References

Shakhnovich, et al. A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents. Paediatr Drugs 2018 Oct;20(5):483–495.

Disclosure(s)

Nothing to disclose
O28 Variability in liver anatomy and physiology in children participating in pharmacokinetic studies
Authors: Friesen A , Radford J , Chan S , Mardis N , Shakhnovich V
Published: May 2019

Background

Obesity-related changes in liver anatomy and physiology (e.g., hepatic fat infiltration) may be important sources of interindivdual variability in hepatic drug metabolism and relevant covariates for physiologically-based pharmacokinetic (PBPK) models. The aim of this investigation was to quantify variability in hepatic fat fraction (HFF) and hepatic volume in children participating in PK studies, utilizing a novel, non-invasive, magnetic resonance imaging (MRI) sequence.1

Methods

Children, without a known diagnosis of fatty liver disease, enrolled in a PK study for hepatic CYP2C19 and CYP3A4 substrates, had hepatic volume and total HFF estimated using MRI proton density fat fraction (PDFF) and HFF assessed via conventional MRI spectroscopy (MRSFF) using a region of interest in the right upper hepatic lobe (LiverLab, Siemens Healthcare). Patient anthropometrics, laboratories and LiverLab outcomes were compared between obese and non-obese children, using independent student t-test, and associations explored via Spearman’s correlation (ρ); SPSSv24, α=0.05. Obesity was defined by body mass index (BMI)≥95th percentile for age; clinically significant liver adiposity defined as HFF>5%.

Results

25 children (7–20 years; 56% obese) had evaluable MRI data. Liver volume ranged 911–2227cm3, MRSFF 1.6–34.8% and PDFF 2.1–31.1%. Liver volume and HFF significantly correlated with BMI (both ρ=0.6, p< 0.01), but not age (both ρ=0.3, p>0.11). Liver volume (1574.5±367.1 vs 1284.8±216.3, p=0.04), MRSFF (8.9±8.4 vs 2.8±1.2, p=0.02), PDFF (8.9±7.0 vs 3.4±1.3, p=0.07) and alanine aminotransferase (ALT; 37.7±15.8 vs 26.8±3.6 IU/L, p=0.02) were higher in obese vs non-obese children. HFF>5% and ALT> 40 were only observed in obese children.

Conclusion

Liver volume and adiposity varied substantially among children and may be important covariates for pediatric PBPK models, especially for obese children. HFF> 5% and ALT> 40 were only observed in obese children. Recently, 24% reduction in clearance of azithromycin, a CYP3A4 substrate, was reported for children with ALT> 40.2 Our PK analyses are in progress.

References

Caussy C, Reeder SB, Sirlin CB, et al. Noninvasive, quantitative assessment of liver fat by MRI-PDFF as as endpoint in NASH trials. Haptology 2018;68(2):763–72.

Zheng Y, Liu SP, Xu BP, et al. Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia. Antimicrob Agents Chemother 2018;62 (9):e00686–18.

Disclosure(s)

Nothing to disclose
O32 Ontogeny of human kidney OCT2 expression across the paediatric age range
Authors: Smeets N , van Groen B , Pertijs J , Wilmer M , Smeets B , Verdijk R , de Wildt S
Published: May 2019

Background

In adults, the organic cation transporter 2 (protein name OCT2, gene name SLC22A2) is localised in the kidney proximal tubules where it mediates organic cation secretion. Hence, the transporter plays a role in the disposition and excretion of several drugs and drug-drug interactions. To better understand the disposition of OCT2 substrate drugs in children, we studied OCT2 localisation and expression in paediatric kidney tissue.

Methods

The expression of OCT2 was visualised in tissue using immunohistochemical staining. Tissues were derived post-mortem from children aged 0 -14 years. Gestational age varied between 24 and 40 weeks. Intensity of the staining at the basolateral membrane was scored by two individual observers using three categories; negative, detectible and high. Agreement between two observers was determined using Cohen’s kappa.

Results

44 kidney samples (n=17 neonates, n=17 infants, n=7 children, n=3 adolescent) were analysed and scored. There was substantial agreement between two judgements with a kappa of 0.773 (p< 0.005). No age related pattern was observed in the expression of OCT2. Even in the youngest age group, the expression of OCT2 was clearly visible.

Conclusion

The kidney expression of OCT2 did not show an age-related pattern. In all age groups, expression levels were similar and OCT2 was properly localised at the basolateral membrane. These findings suggest that, with increasing age, OCT2 will not influence the renal excretion of its substrates.

Disclosure(s)

Nothing to disclose
O38 Population pharmacokinetics of ganciclovir after oral valganciclovir in renal transplant children
Authors: Facchin A , Elie V , Benyoub N , Baudouin V , Maisin A , Magreault S , Jacqz-Aigrain E
Published: May 2019

Background

Cytomegalovirus (CMV) infection is a major cause of morbidity in solid organ transplant recipients. Valganciclovir (ValG), prodrug of the antiviral ganciclovir, is used to prevent or treat CMV infection in this population. is controversial in children, As the percentage of patients reaching the pharmacological target is too low with currently used ValG dosing regimen, our aim was to determine ganciclovir population pharmacokinetics in renal transplant children receiving ValG and propose an appropriate dosage regimen.

Methods

After transplantation, children receiving ValG were monitored for plasma ganciclovir concentrations using high performance liquid chromatography. Population pharmacockinetics analysis was performed with NONMEM.

Results

1212 samples from 104 renal transplant patients, aged 2 to 20 years, received ValG to prevent (n=80), treat (n=12), or both prevent then treat (n=12) CMV infection. ValG was administered orally at a daily dose of 19.8 ± 10.1 mg/kg (mean ± SD). A two-compartment model with first-order elimination best fitted the data. At steady-state, AUC24h-ss was 64.5 ± 23.4 µg/mL.h, apparent clearance (CL/F) was 0.39 ± 0.14 L/h/kg, apparent volume of distribution at steady-state (VDss/F) was 2.4 ± 0.48 L/kg. Ganciclovir CL/F increased with body surface area, decreased with increasing creatinine concentration and was 15% higher in boys. Central volume of distribution increased with body surface area (BSA) and showed a 14% increase in boys. Internal validation was performed.

Conclusion

We have successfully built a pharmacokinetic model allowing to propose dosages adapted individually to the characteristics of renal transplanted children.

Disclosure(s)

Nothing to disclose
P02 Allopurinol counteracts inadequate mercaptopurine metabolism in paediatric acute lymphoblastic leukemia
Authors: Adam de Beaumais T , Petit A , Simonin M , Médard Y , Benchikh A , Dollfus C , Leverger G , Jacqz-Aigrain E
Published: May 2019

Background

Mercaptopurine (6-MP), a cornerstone of childhood acute lymphoblastic leukemia (ALL) therapy, is metabolized to active 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotides (6-MMPN) potentially hepatotoxic (threshold of 5000 pmol/8x108 RBC). In few cases, the equilibrium between 6-TGN and 6-MMPN is unbalanced and in favor to 6-MMPN with high risk of inefficacy and toxicities. Here, we treated patients with allopurinol which inhibits Xanthine Oxidase and Thiopurine S-methyl Transferase (TPMT) implicated in methylation of thiopurines.

Methods

Therapeutic drug monitoring of ALL patients was based on the determination of metabolites concentrations in red blood cells, measured by HPLC-UV after 3 weeks of stable 6-MP dose. After parental consent, individual genotypes are determined for TPMT (*2, *3B, *3C), ITPA (c.94C>A) and HLA*B5801 (prior to allopurinol) by TaqMan allelic discrimination.

Results

In 8 patients, 6-MMPN/6-TGN ratio was too high, superior to 50 (range: 58–248) with 6-TGN under therapeutic threshold (< 250 pmol/8x108 RBC). All patients have a wild-type TPMT genotype and for 3 patients, ITPA polymorphism could be involved to this disequilibrium. The co-administration of Allopurinol (50 mg n=5, 100 mg n=2), with a reduced 6-MP dose (around -50%) dose had a positive impact on metabolic ratio, inferior to 15 (range: < 1- 13) with metabolites levels inside therapeutic window and on resolving some toxicities (hypoglycemia (n=4), hepatotoxicity (n=3)). For one patient, 200 mg of Allopurinol was administered without reducing 6-MP dose, the metabolic ratio decreased from 115 to 63 but metabolites levels were both at supratherapeutic levels.

Conclusion

Allopurinol was effective in redirecting 6-MP metabolism to 6-TGN. A standardized protocol for this co-administration needs to be established and DNA-TGN incorporation dosage could be helpful for this recommendation. Long-term follow-up is required to evaluate impact on safety and efficacy of ALL maintenance therapy.

Disclosure(s)

Nothing to disclose
P03 Germline NUDT15 mutation and thiopurines for children with acute lymphoblastic leukemia: is it a prognostic factor?
Authors: Simonin M , Petit A , Médard Y , Benchikh A , Minckes O , Auvrignon A , Donadieu J , Leverger G , Jacqz-Aigrain E , Adam de Beaumais T
Published: May 2019

Background

The nudix hydrolase 15 (NUDT15) polymorphism recently emerges as a biomarker of severe hematological toxicity during 6-mercaptopurine (6-MP) therapy of children with acute lymphoblastic leukemia (ALL). Initially described restricted to Asian population, recent publications highlighted its presence in patients with European ancestry. In November 2018, the Clinical Pharmacogenetics Implementation Consortium (CPIC) updated the guideline for thiopurines dosing based on Thiopurine S-methyl transferase (TPMT) and NUDT15 genotypes. Here, we presented a feedback from a French monocentric experience in ALL patients.

Methods

We retrospectively genotyped 188 children for NUDT15 c.94C>A treated for ALL at Trousseau hospital, Paris. Parents have given their consent for thiopurines’ therapeutic drug monitoring including performing TPMT genotype (*2, *3B, *3C). We focused, for patients with a mutated NUDT15 genotype, on treatment response in terms of morbi-mortality.

Results

This NUDT15 polymorphism was found for 6 patients (3.2%): one patient with a European ancestry and the others with an Asian ancestry. Five children had a NUDT15 mutated heterozygous genotype without TPMT alterations and one patient with a mutated homozygous NUDT15 genotype associated with TPMT *1/*3C. Hematological and/or infectious complications were reported for all patients with this variant with hospitalization in intensive care unit for the one with a mutated NUDT15 genotype and TPMT *1/*3C. Reduced 6-MP dose (between 30% to 50% of the standard dose for heterozygous patients and 3% of the standard dose for mutated homozygous patient) was required for maintenance therapy. Two patients had a relapse.

Conclusion

This report supports CPIC guidelines for screening NUDT15 polymorphism before 6-MP treatment regardless patients‘ race. The impact of this polymorphism on relapse occurrence is worrying and prospective results with dose adjustments at 6-MP initiation will be crucial to understand if treatment interruptions and/or reduced dose were at risk of relapse.

Disclosure(s)

Nothing to disclose
P06 Paternal exposure to methotrexate and the risk of miscarriage – a register based nationwide cohort study
Authors: Andersen J , Askaa B , Jensen TB , Horwitz H , Vermehren C , Broedbaek K
Published: May 2019

Objective

To study the association between paternal exposure to methotrexate within three month before conception and during the first trimester of pregnancy and the risk of miscarriage.

Methods

We conducted a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2015. All births were identified using the Medical Birth Registry, and all records of induced abortion and miscarriage were from the National Hospital Register. Data on drug use were from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women with a partner exposed to methotrexate. The study was approved by the Danish Data Protection Agency (2015-41-4309).

Results

We identified 1,364,063 registered pregnancies with known paternity, of whom 520 fathers were exposure to methotrexate within the three months before conception to the end of the first trimester. Among these, 46 (8.9%) experienced a miscarriage compared to 122,926 (9.0%) among the unexposed.

There was no increased risk of experiencing a miscarriage in pregnancies to men exposed to methotrexate before pregnancy compared to unexposed (adjusted hazard ratio 0.99 (CI95% 0.67- 1.46)). Furthermore, we found no increased risk of experiencing a miscarriage in pregnancies to men exposed to methotrexate during first trimester compared to unexposed (adjusted hazard ratio 0.90 (CI95% 0.61–1.32)).

Conclusion

We found no association between paternal exposure to methotrexate before and during early pregnancy and miscarriage. Available data suggest that paternal methotrexate exposure should not be of major concern. Multinational recommendations could be changed accordingly.

Disclosure(s)

Nothing to disclose
P08 Is there a difference in the frequency of manipulated orally and rectally administered medicines to paediatric in-patients in Sweden in the year 2009 and 2018 respectively? A register study
Authors: Andersson A , Eksborg S , Lindemalm S , Förberg U
Published: May 2019

Background

Since there is a lack of drugs in suitable strengths and child-friendly dosage forms, manipulation is sometimes necessary in paediatrics. A manipulation is the physical alteration of a drug dosage form with the purpose to extract and administer the prescribed proportion of a drug dose.

The purpose of this study was to calculate the frequency of manipulated medicines administered to paediatric in-patients at a large Children´s Hospital for two separate years and compare whether there has been a change in practice.

Material and Methods

Data were collected for all administered doses during 2 separate years (2009 and 2018) at the paediatric wards at our Children´s Hospital, from a hospital-based electronic register. All administered doses where the number of tablets or suppositories were decimal were added and calculated as a percentage of the total number of oral and rectal administrations. Data are anonymous but information regarding gender, age, hospital ward and number of drugs per patient were available and were analysed.

Results

In one year, approximately 450 000 doses of medicine are administered to paediatric patients in our Children´s hospital.

The results will be analysed with regards to differences between patient age, gender, prescribing year and drug substance. A pilot study showed that 10% of all solid oral administrations to patients 6 - 12 years old, were part of a tablet. For patients 0 - 2 years over 20% of all solid rectal administrations were part of a suppository.

The extent of manipulation is affected by a lot of factors, where the most prominent is whether there are strengths suitable for that age-group available on the market or not.

Conclusion

Most often there is a lack of knowledge how manipulation of medicines influences the dosing accuracy and often we do this to our most vulnerable patients.

Disclosure(s)

Nothing to disclose
P09 Serum neurofilament light chain levels are an independent predictor of neurodevelopmental outcome in preterm infants
Authors: Hauck A , Goeral K , Atkinson A , Fuiko R , Leeb C , Michalak Z , Klebermass K , van den Anker J , Berger A , Kuhle J , Olischar M , Wellmann S
Published: May 2019

Background and Purpose

Serum neurofilament light chain (sNfL) has recently emerged as a promising biomarker reflecting structural neuro-axonal damage in different neurological diseases. Our study aimed at assessing whether sNfL can predict the functional outcome in preterm infants who suffered from neonatal haemorrhagic brain injury.

Methods

In this prospective observational study, we used an ultrasensitive single-molecule array assay to measure serum and cerebrospinal fluid (CSF) concentrations of NfL in preterm infants diagnosed with intraventricular haemorrhage (IVH) in the first few days of life. We determined the temporal profile of serum and CSF NfL levels from first diagnosis of IVH until term equivalent age, their association with cerebral imaging markers, and with clinical and functional outcome until 2 years of age assessed by Bayley Scales of Infant Development. We fitted univariable and multivariable logistic regression models to determine risk factors for low motor and cognitive development. Longitudinal mixed effects models modelled NfL levels using cubic spline smoothers to track the trajectory over time.

Results

The study included 48 infants born with less than 32 weeks of gestation. At the time point of IVH diagnosis, NfL median levels were 271.9 pg/mL (IQR 151.2–389.7), and strongly decreased until term equivalent age to 15.7 pg/mL (IQR 11.1–32.2). CSF values were 113-fold higher (IQR 40–211) than corresponding serum values. Additional cerebral infarction (n=23) but not post-haemorrhagic hydrocephalus with permanent external ventricular drainage (n=29) or other diseases independently determined sNfL levels. In multivariate logistic regression models, the only significant predictor of poor motor outcome at 2 years or death was sNfL level (p=0.02).There was a clear difference between the NfL trajectory for those with poor motor outcome at 1 year.

Conclusions

This study shows that early sNfL is an independent prognostic biomarker for motor functional outcome in preterm infants after IVH.

Disclosure(s)

Nothing to disclose
P14 Pharmacovigilance in pediatric patients: the challenge of identifying new signal
Authors: Kronenfeld N , Gamsu S , Flor-Hirsch H , Agajani N , Sheinberg R , Ben-Nun L , Goldman M , Berkovitch M
Published: May 2019

Introduction

The importance of reporting adverse drug reactions (ADRs) is well known. However, the reporting rate is very low, and therefore, identifying new signal is challenging.

Objective

To create an interventional program in order to improve reporting rate and trying to identify new signal.

Material and methods

The interventional program was implemented at the Pediatric Division of Assaf Harofeh Medical Center and included presentations to the healthcare professionals, posters, creating new ADRs reporting methods and alerts.

Results

Reporting rate of ADRs during the year before implementation of the program was negligible. During the study period (three months), the reporting rate increased dramatically. A new signal was reported; two neonates with apnea related to IVIG administration in the neonatology department. The distribution of reports was: 50% from the general pediatric department, 26% - pediatric neurology department, 21% and 6%, from the pediatric and neonatal intensive care units, respectively. Steroids and antibiotics were responsible for various ADRs, but not for a new signal.

Conclusion

There is one case report in the literature on apnea related to IVIG administration. Adverse reactions in children are a major problem and sometimes can lead to morbidity mortality. Identifying new signal in pediatric patients is not common, and very challenging.

Disclosure(s)

Nothing to disclose
P19 Drug use in adolescents attending the emergency department for mental health problems
Authors: Buttera M , Clavenna A , Maselli E , Tansini L , Canevini MP , Bonati M
Published: May 2019

Background

Scant evidence is available regarding the pharmacological management of acute episodes of mental disorders in children and adolescents attending emergency departments (ED). In this regard, we performed a retrospective study with the aim to evaluate the pattern of psychotropic drug use in an ED of a large hospital.

Methods

A retrospective chart review of adolescents (13–17 years) visited in the ED of San Paolo University Hospital in Milan for a mental disorder between January and June 2018 was conducted. In particular, information concerning age, gender, type of mental disorder, psychotropic drugs administered in the ED and outcome of the visit were extracted and analysed, using an anonymous patient code.

Results

A total of 1,298 adolescents 13–17 years old were visited during the observation period, 56 (4%) of whom had a diagnosis of mental disorder (35 females and 21 males).

The most common disorder was predominant psychomotor disturbance (International Classification of Diseases 9 (ICD9) revision code 308.2; 12 patients), followed by anxiety disorder in conditions classified elsewhere (293.84, 8 patients) and anxiety states (300.0, 7 patients).

Ten adolescents were hospitalised, while 16 (29%) received a psychotropic drug in the ED: 14 patients received a benzodiapine (8 delorazepam, 3 lorazepam), and 2 an antipsychotic drug (risperidone+olanzapine; promazine). Five out of 12 adolescents with psychomotor disturbance received a psychotropic drug (3 delorazepam, 1 lorazepam, 1 risperidone+olanzapine).

Although no randomized controlled trial has evaluated the safety and effectiveness of benzodiazepines in the paediatric population, delorazepam was identified as the first choice pharmacological treatment for agitation in children and adolescents in a local protocol.

Conclusion

Nearly all children received drugs for which no controlled trials have been performed in the paediatric population and for which the appropriateness is debatable. More evidence is needed to guide the pharmacological management of acute episodes of mental disorders.

Disclosure(s)

Nothing to disclose
P24 Caffeine in preterm neonates: impact on sleep wake regulation
Authors: Datta AN , Koch G , Schönfeld N , Jost K , Atkinson A , Schulzke SM , Pfister M
Published: May 2019

Background

Sleep wake regulation undergoes distinctive maturational changes. Ultradian sleep wake rhythm predominates at preterm age and is mainly driven by the internal clock. Increased perinatal morbidity in preterm neonates often appears with breathing disorders, among which apnea of prematurity (AOP) is the most frequently observed. Pharmacological support with caffeine has been successfully employed in the treatment of AOP. Nowadays, caffeine citrate is administered to all preterm neonates suffering from AOP. Objective of our study was a quantitative investigation of whether caffeine citrate treatment for reduction of apnea and bradycardia of prematurity affects sleep-wake behavior in preterm neonates.

Methods

Observational study of 64 preterm neonates during their first five days of life with gestational age (GA) < 32 weeks or very low birth weight of < 1500 g. Total of 52 patients treated with caffeine and 12 controls without caffeine were included. Sleep-wake behavior was scored in wakefulness (W), active sleep (AS), and quiet sleep (QS) associated with physical and cerebral regeneration. Individual caffeine concentration of every neonate was simulated with a pharmacokinetic model.

Results

For increasing caffeine concentration, W increased, AS decreased, and QS was unchanged for GA > or = 28 weeks. No caffeine effect for GA < 28 weeks could be demonstrated. Maturational effects could be seen when comparing preterm neonates of GA >32 weeks with a birth weight of < 1500 g with very preterm neonates born of GA < 32: Neonates born >32 weeks had a significantly higher amount of W and lower percentage of AS.

Conclusions

Treatment of apnea and bradycardia as well as stabilization of respiration with standard caffeine treatment is not at cost of QS, i.e. time for physical and cerebral regeneration during sleep remains unchanged. There is an increased fraction of W, alertness and most probably also arousability.

Disclosure(s)

Nothing to disclose
P26 Pilot on harmonising dosing recommendation for term and preterm neonates in the Netherlands (Neodose project)
Authors: de Hoop-Sommen MA , van der Zanden TM , Allegaert K , Flint RB , Simons SHP , de Wildt SN , Consortium NeoDose
Published: May 2019

Background

Many drugs are used off-label in term and preterm neonates, and dosing recommendations for many drugs are lacking in the Dutch Paediatric Formulary (DPF). This results in widely varying dosing regimens used across neonatal intensive care units (NICUs) in the Netherlands. The Neodose pilot project aimed to develop best-evidence national dosing recommendations for (pre)term neonates. Because scientific evidence is scarce, a consensus-based approach was used.

Methods

A priority drug list, containing the most frequently used drugs for neonates, was drafted. From this list 22 drugs were selected for further research within the Neodose pilot project. The pilot utilized a two-step approach: First, consensus was established with all Dutch NICUs for neonatal dosing recommendations. Local treatment protocols were retrieved, compared and discussed, leading to consensus-based dosing recommendations. Secondly, we aimed to develop best-evidence dosing recommendations for the following five drugs: acyclovir, ganciclovir, ibuprofen, hydrocortisone and dexamethasone.

Results

For 21 of 22 drugs, local dosing guidelines differed significantly. Mostly concerning total daily dose, dosing frequency and route of administration. Little or no distinction is made between treatment of preterm and term neonates. Approximately half of the consensus-based dosing recommendations (45%) differ in some degree from all local protocols. Comparing the consensus-based dosing recommendations with the available evidence, almost half of the consensus doses were adjusted. The grounds on which dosing recommendations were adjusted differed. Acyclovir-dosing adjustment was based on pharmacokinetics. Hydrocortisone-dosing was adjusted due to new insights after the evidence has been put together. For dexamethasone-dosing, the consensus dose was eventually chosen, because every available trial used a different dosing regimen.

Conclusion

This pilot showed that, when evidence is inconclusive, consensus on dosing regimens in neonates can be obtained by comparing local regimens and analysing the available evidence. For more uniform use, these new recommendations will be published in the DPF.

Disclosure(s)

This project was funded by the federation of medical specialists for qualitative improvement (Stichting Kwaliteitsgelden Medisch Specialisten (SKMS).
P27 The juvenile pig as animal model for unraveling renal drug elimination processes in children
Authors: Dhondt L , Croubels S , De Paepe P , De Cock P , Devreese M
Published: May 2019

Background

Over the years pigs were promoted as potential animal model for humans due to their high degree of anatomical and physiological similarities with humans. Gasthuys et al. demonstrated that the maturation of the kidney function in terms of the glomerular filtration rate (GFR) in growing pigs was comparable to humans, but no data are currently available on renal plasma flow, renal tubular secretion and reabsorption.1 The aim of this pilot study was to unravel the contribution of distinct renal elimination processes in juvenile pigs and to compare with reported human values.

Methods

Eight seven-week-old pigs were intravenously administered a single bolus of a cocktail of following renal markers: iohexol (64.7 mg/kg body weight (BW), GFR), para-aminohippuric acid (PAH, 10 mg/kg BW, effective renal plasma flow (ERPF) and anion secretion), pindolol (0.05 mg/kg BW, cation secretion) and fluconazole (0.5 mg/kg, tubular reabsorption). Plasma and urinary concentrations were determined for PAH, pindolol and fluconazole at several time points. Only plasma concentrations were assessed for iohexol. PK modelling was performed with Phoenix® WinNonlin®.

Results

The clearance of iohexol was 97.9 ± 16.1 ml/min/m² (mean ± SD). The ERPF, calculated as the renal clearance of PAH, was 9.5 ± 2.1 ml/min/kg. These GFR and ERPF values are approximately a factor 1.3 higher than the values observed in humans, namely 63.5–75.0 mL/min/m² and 6.5 ± 2.0 mL/min/kg.2,3 The net tubular secretion of PAH was 5.4 ± 1.8 mL/min/kg, which was comparable with the values obtained in humans (5.0 ± 1.8 mL/min/kg).3 Results for cation secretion and tubular reabsorption are not yet available (to be presented at the congress).

Conclusion

The net tubular secretion of PAH was comparable between the juvenile pigs and humans. The GFR and ERPF were generally a factor 1.3 higher in juvenile pigs compared to humans.

References

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.

Schwartz GJ, Furth SL. Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatric Nephrology 2007;22(11):1839–1848.

Gross AS, et al., Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol. British Journal of Clinical Pharmacology 2001. 51(6):547–555.

Disclosure(s)

This study was funded by the Special Research Fund of Ghent University (BOF16/DOC/285).