Limited Sampling Strategies to Predict Ganciclovir Exposure after Valganciclovir Administration and to Reduce Monitoring Constraints in Renal Transplant Children.

Valganciclovir, the ganciclovir prodrug, is an antiviral agent used to prevent cytomegalovirus infection in renal transplant children. Therapeutic drug monitoring is still necessary to ensure optimal therapeutic area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 60 µg·h/mL since valganciclovir presents a high pharmacokinetic variability. To calculate ganciclovir AUC0-24 with the trapezoidal method, 7 samples are needed. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy (LSS) for individualizing valganciclovir dose in renal transplant children. Rich pharmacokinetic data from ganciclovir plasmatic dosages measured in renal transplant children who received valganciclovir to prevent cytomegalovirus infection at Robert Debré University Hospital were collected retrospectively. Ganciclovir AUC0-24s were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC0-24. The patients included were divided into two groups for model development (50 patients) and validation (30 patients). A total of 80 patients were included between February 2005 and November 2018. Multilinear regression models were developed on 50 pharmacokinetic profiles (50 patients) and validated with an independent group of 43 pharmacokinetic profiles (30 patients). Regressions based on samples collected at T1h-T4h-T8h, T2h-T4h-T8h, or T1h-T2h-T8h presented the best AUC0-24 predictive performances with an average difference between reference and predicted AUC0-24 of -0.27, 0.34, and -0.40 µg·h/mL, respectively. In conclusion, valganciclovir dosage adaptation was required in children to achieve the target AUC0-24. Three LSS models using three pharmacokinetic blood samples instead of seven will be useful for individualizing valganciclovir prophylaxis in renal transplant children.

Population pharmacokinetics of ceftazidime in critically ill children: impact of cystic fibrosis.

BACKGROUND: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections. OBJECTIVES: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens. METHODS: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software. RESULTS: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children. CONCLUSIONS: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children.

Population pharmacokinetics of ganciclovir after valganciclovir in renal transplant children.

BACKGROUND: Valganciclovir, the ganciclovir prodrug, is an antiviral agent administered orally to prevent or treat cytomegalovirus infection in solid organ transplant recipients. Dosing regimen of valganciclovir is still controversial in children, as the number of patients reaching the Area Under the Curve at steady state (AUCss) target (40 - 60 mg.h/L) remains highly variable. The aim of this study was to determine the population pharmacokinetics of valganciclovir in paediatric renal transplant recipients and propose an appropriate dosing regimen. METHODS: Renal transplant children who received valganciclovir to prevent or treat cytomegalovirus infection at Robert Debré University Hospital were included. Plasma ganciclovir concentrations were determined by high performance liquid chromatography and ultraviolet detection. Population pharmacokinetic analysis was performed with NONMEM software. RESULTS: 104 patients, aged 2 to 20 years, treated with valganciclovir administered at a mean dose of 17.3 ± 6.1 mg/kg to prevent and/or treat cytomegalovirus infection after renal transplantation were included. A total of 1212 samples were available. A two-compartment model with first-order elimination best fitted the data: ganciclovir clearance increased with body surface area, was 15% higher in boys and decreased with increasing creatinine concentration. Central volume of distribution increased with body surface area and was 14% higher in boys. According to the personalized dosing regimen, 65.7% and 65.4% of children were predicted to achieve the AUCss target for cytomegalovirus prophylaxis and treatment, respectively. CONCLUSION: A new pharmacokinetic model was built allowing to propose individualised dose adapted to renal transplanted paediatric patients characteristics.

Variability of ciprofloxacin pharmacokinetics in children: impact on dose range in sickle cell patients.

Objectives: To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens. Patients and methods: Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA). Results: Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0 mg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; n = 20, 33%), haemopathy (n = 15, 25%), cystic fibrosis (CF; n = 3, 5%) and other diseases (n  =  22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (mean ±â€Šâ€ŠSD) was 0.81 ±â€Š0.30 L/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed. Conclusions: In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients.

Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial.

AIMS: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis. METHODS: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg-1 ; maintenance dose 12 mg kg-1 day-1 or 20 mg kg-1 day-1 , respectively, for infants <30 weeks or ≥30 weeks' corrected gestational age) or micafungin (loading dose 15 mg kg-1 day-1 ; maintenance dose 10 mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks' corrected gestational age or hospital discharge. RESULTS: Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported. CONCLUSION: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.

Pharmacogenetics of posttransplant diabetes mellitus.

Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome.

A Computer Prescribing Order Entry-Clinical Decision Support system designed for neonatal care: results of the 'preselected prescription' concept at the bedside.

WHAT IS KNOWN: The neonatal intensive care units (NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects (pADEs) in NICUs. However, Computer Prescribing Order Entry-Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited. OBJECTIVES: We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications. METHODS: A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place. RESULTS: Seven hundred and sixty successive newborns (from 24 to 42 weeks' gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. WHAT IS NEW?: The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations. CONCLUSIONS: This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs.

Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates.

OBJECTIVES: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens. METHODS: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations. RESULTS: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg ·â€Šh/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups. CONCLUSIONS: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.

Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines.

UNLABELLED: The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. CONCLUSION: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.

Simplified Dosing Regimens for Gentamicin in Neonatal Sepsis.

Background: The effectiveness of antibiotics for the treatment of severe bacterial infections in newborns in resource-limited settings has been determined by empirical evidence. However, such an approach does not warrant optimal exposure to antibiotic agents, which are known to show different disposition characteristics in this population. Here we evaluate the rationale for a simplified regimen of gentamicin taking into account the effect of body size and organ maturation on pharmacokinetics. The analysis is supported by efficacy data from a series of clinical trials in this population. Methods: A previously published pharmacokinetic model was used to simulate gentamicin concentration vs. time profiles in a virtual cohort of neonates. Model predictive performance was assessed by supplementary external validation procedures using therapeutic drug monitoring data collected in neonates and young infants with or without sepsis. Subsequently, clinical trial simulations were performed to characterize the exposure to intra-muscular gentamicin after a q.d. regimen. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. Results: In contrast to current World Health Organization guidelines, which recommend gentamicin doses between 5 and 7.5 mg/kg, our analysis shows that gentamicin can be used as a fixed dose regimen according to three weight-bands: 10 mg for patients with body weight <2.5 kg, 16 mg for patients with body weight between 2.5 and 4 kg, and 30 mg for those with body weight >4 kg. Conclusion: The choice of the dose of an antibiotic must be supported by a strong scientific rationale, taking into account the differences in drug disposition in the target patient population. Our analysis reveals that a simplified regimen is feasible and could be used in resource-limited settings for the treatment of sepsis in neonates and young infants with sepsis aged 0-59 days.

Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients.

The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians' compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians' compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1+/-14.6mgh/L versus 36.7+/-16.3mgh/L, p=0.0035) and to more AUCs in the target range (69% versus 56%, p=0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.

Renal transplantation in children: critical analysis of age related surgical complications.

To determine age-related risk factors of urological and vascular complications. We performed a retrospective analysis of the data of 202 renal transplantations in 193 children between 1989 and 2007 at a single institution. Out of 193 grafts (combined renal and liver grafts were excluded), we observed urological complications in 42 cases (21.7%) leading to graft loss in one case and vascular complications in 27 cases (13.9%) leading to graft loss in seven. The urological complications were VUR (n=25, 12.4%), ureteral stricture (n=10, 5%), anastomotic leak (n=4, 2%), ureteral necrosis (n=2, 1%), and incrustative pyelitis (n=1, 0.5%). Vascular complications were arterial stricture (n=14, 7.2%), arterial thrombosis (n=4, 2%), venous thrombosis (n=2, 1%), and others (n=7). Donors aged less than six yr were a risk factor of vascular complications leading to graft loss (p=0.0001), whereas patients with PUV had more urological complications (p=0.001). Overall patient and graft survival is 93.1% and 84% at five yr, respectively. Surgical complications remain a major cause of graft loss (12%) and morbidity in children's kidney transplantation (38.9%). Young age of donors is the major risk factor of early graft loss as a result of vascular complication. However, donor selection based on age is limited by the shortage of organs.

Bioavailability of oral vitamin E formulations in adult volunteers and children with chronic cholestasis or cystic fibrosis.

PURPOSE: To test bioequivalence of oral vitamin E formulations, water-soluble tocofersolan (test) and water-miscible (reference), in healthy adult volunteers, and their bioavailability in children with chronic cholestasis or cystic fibrosis. METHODS: In a two-way open randomized single dose cross-over design, 1200 IU were administered in 12 healthy volunteers and 100 IU/kg in 12 children with chronic cholestasis or cystic fibrosis. RESULTS: In healthy volunteers, formulations were not bioequivalent with a higher exposure to tocofersolan. In cholestatic children tocofersolan bioavailability was significantly higher than reference formulation (maximum plasma concentration: P = 0.008 and AUC: P = 0.0026). Bioavailability was not statistically different in cystic fibrosis. CONCLUSIONS: Oral tocofersolan was more bioavailable than the reference formulation in children with chronic cholestasis and similarly bioavailable in cystic fibrosis. Tocofersolan may represent an alternative to painful intramuscular vitamin E injections in chronic cholestasis, or to other oral formulations in cystic fibrosis.

Determination of ketamine and norketamine in plasma by micro-liquid chromatography-mass spectrometry.

A sensitive method of determination of ketamine and norketamine by micro-liquid chromatography/mass spectrometry was developed as part of a clinical trial in a pediatric population. Compounds were extracted from 100 microl plasma samples using solid-phase extraction on Oasis MCX cartridges. Separation was achieved on a C18 micro-column with a mobile phase composed of formic acid 0.1% and acetonitrile (90/10, v/v). Detection of ketamine, norketamine and their internal standard norketamine D4 was performed using selected ion monitoring at m/z 238.2, 224.2 and 228.2, respectively. Under these conditions, no loss of signal due to matrix effect was found and time of analysis did not exceed 10 min. Extracted calibration curves were linear from 5 to 500 ng/ml for each analyte, with correlation coefficients over 0.999. Intra- and inter-day validation studies showed mean recoveries between 98.1 and 101.7% and a relative standard deviation below 1.9%. Extraction recoveries ranged from 84.8 to 89.8% for both ketamine and norketamine. Limit of quantification was 4 ng/ml for each analyte.

[Molecular pharmacogenetics in hospital laboratories in France: current data and future prospects]. / La pharmacogénétique moléculaire hospitalière en France: données actuelles et perspectives.

Molecular pharmacogenetic units have recently been established in several hospital laboratories in France. The clinical impact of these units is still limited and numerous problems of organizational, ethical, legal, technical, social and economical nature remain to be resolved. However, an increasing number of these units, a rise in their activities and an enlargement of their scope of application are foreseeable in the future. Ultimately, these units would significantly contribute to limit the public health problem caused by interindividual variabilities in drug effects. In view of these prospects, it seems essential that such hospital activity should be quickly recognised by the authorities and the various health sectors in France. It is also essential that the problems that arise from such pharmacogenetic activities should be considered by the authorities and would profit from the organization of a national network and from financial guarantees.

[Dosing regimens of antibiotics in neonates: Variations in clinical practice and what should be done?]. / Posologie des antibiotiques chez le nouveau-né : variations des pratiques et comment y remédier ?

There is wide variation in neonatal dosages of antibiotics in clinical practice, both nationally and internationally. This reflects the lack of evaluation of drugs in this therapeutic class, although widely prescribed. Given this situation, optimization of antibiotic prescription is required to ensure efficacy and safety of neonatal treatment and reduce microbial resistance. Rational prescription should be based on the knowledge of developmental pharmacokinetics and pharmacodynamics. Rigorous studies, conducted in collaboration between neonatologists and pharmacologists, are essential to develop and validate evidence-based neonatal dosage regimens.

Effects of drugs on the fetus.

Most drugs are not labelled for use in pregnancy. Consequently, large numbers of women expose their fetus to potential risks, either because they do not know that they are pregnant or because they require treatment for gestational pathologies. The present review focuses on drug classes for which the risk:benefit ratio during pregnancy has been discussed recently based on human data. Selective serotonin reuptake inhibitors have gained wide acceptance in the treatment of depression and data on their risk for neonatal adaptation after late exposure are reviewed. Angiotensin converting enzyme inhibitors and angiotensin II receptors antagonists interact with the renin-angiotensin system, although with different mechanisms, and might cause severe fetal tubular dysgenesis. Non-steroidal anti-inflammatory and antiviral drugs and recreational drugs are also presented.

Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine.

6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.

[Consent in children: Practical situations (part 2)]. / Recherche en pédiatrie (2) : le consentement en pratique.

Ethical and regulatory documents frame informed consent in pediatric research; their application is obligatory but may be complex. In this specific context, pediatric investigators have a central ethical role to play to ensure the strict respect of regulatory and ethical requirements adapted to the French legal, social, and cultural context as well as good clinical practices. This article attempts to shed light on the considerations that can allow researchers to come to terms with industrial and institutional demands while responding to the needs of patients, particularly in the domain of pediatric research.

[Legal aspects of consent in children (Part 1)]. / Recherche en pédiatrie (1) : dispositions juridiques relatives au consentement.

In pediatric research, the patient is legally a minor and therefore protected by law. Research can only be conducted after parental consent and patient assent have been obtained. In this context, this review discusses the historical events and documents related to all ethical precautions and obligations. It also underlines that physicians shall respect all legal measures, but that individual involvement must comply with ethical standards while taking into account issues particular to pediatric research related to parental consent and child assent to clinical trials.