[Pediatric exposure to endocrine disruptors and carcinogenic, mutagenic or reprotoxic substances by pharmaceutical forms intended for the cutaneous route: Regulatory provisions in France, in Europe, and state of the art of scientific knowledge]. / Exposition pédiatrique aux perturbateurs endocriniens et substances cancérogènes, mutagènes ou reprotoxiques par des formes pharmaceutiques destinées à la voie cutanée : dispositions réglementaires en France, en Europe, et état de l'art des connaissances scientifiques.

OBJECTIVES: The objective is to conduct a review of pediatric exposure to substances whose endocrine disrupting (ED), carcinogenic, mutagenic, or reprotoxic (CMR) character has been confirmed or remains controversial, through their use in pharmaceutical forms intended for the cutaneous route, as well as regulatory measures diligent at the national and European levels. METHODS: A bibliographical search was carried out on the databases PubMed, Web of Science, Cochrane Library, supplemented by a search for recommendations from French and European authorities. References were selected following an assessment of their relevance to our topic. RESULTS: Seventy-one references were selected. Pediatric exposure to endocrine disruptors and CMR substances remains through products formulated for their use, but also through indirect exposure to products commonly used by adults. Exposure arises both from the choice of excipients (parabens, phenoxyethanol), packaging materials (bisphenols, phthalates) and the qualitative or quantitative nature of the active ingredients (iodine, boron, pyrethroids, organic sunscreens). CONCLUSION: The health professional must be able to develop a critical mind on such substances in order to inform and promote therapeutic adherence, guaranteeing the safety of the child's care.

Determination of the optimal dose of ephedrine in the treatment of arterial hypotension due to general anesthesia in neonates and infants below 6 months old: the ephedrine study protocol for a randomized, open-label, controlled, dose escalation trial.

BACKGROUND: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. METHODS: The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. DISCUSSION: This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. TRIAL REGISTRATION: ClinicalTrials.gov NCT02384876 . Registered on March 2015.

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.

Risk assessment of neonatal excipient exposure: lessons from food safety and other areas.

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Cost analysis of neonatal and pediatric parenteral nutrition in Europe: a multi-country study.

OBJECTIVES: Parenteral nutrition (PN) is critical in neonatal and pediatric care for patients unable to tolerate enteral feeding. This study assessed the total costs of compounding PN therapy for neonates, infants and children. METHODS: Face-to-face and telephone interviews were conducted in 12 hospitals across four European countries (Belgium, France, Germany and UK) to collect information on resources utilized to compound PN, including nutrients, staff time, equipment cost and supplies. A bottom-up cost model was constructed to assess total costs of PN therapy by assigning monetary values to the resource utilization using published list prices and interview data. RESULTS: A total of 49,922 PN bags per year were used to treat 4295 neonatal and pediatric patients among these hospitals. The daily total costs of one compounded PN bag for neonates in the 12 hospitals across the four countries equalled euro 55.16 (Belgium euro 53.26, France euro 46.23, Germany euro 64.05, UK L 37.43/\[euro]42.86). Overall, nutrients accounted for 25% of total costs, supplies 18%, wages 54% and equipment 3%. Average costs per bag for infants <2 year were euro 84.52 (euro 74.65 in Belgium, euro 83.84 in France, euro 92.70 in Germany and L 52.63/euro 60.26 in the UK), and for children 2-18 years euro 118.02 (euro 93.85 in Belgium, euro 121.35 in France, euro 124.54 in Germany and L 69.49/euro 79.56 in the UK), of which 63% is attributable to nutrients and 28% to wages. CONCLUSION: The data indicated that PN costs differ among countries and a major proportion was due to staff time (L 1=euro 1.144959).

[Pharmacokinetic changes in renal failure]. / Modifications pharmacocinétiques au cours de l'insuffisance rénale.

DRUG PHARMACOKINETICS: One of the first steps in the clinical development of drugs consists in studies of their pharmacokinetics. Dosage and administration interval necessary to ensure secure and efficient plasma levels are derived from the values of pharmacokinetic parameters. Renal disease usually implies multiple pathophysiological modifications that generate alteration in drugs pharmacokinetic profile. Those modifications mainly occur on elimination phase but also to a significant extent on absorption and distribution. PATHOPHYSIOLOGICAL CHANGES: In this article we describe potential alteration in drugs absorption, distribution (volume of distribution, binding to plasma proteins), hepatic or renal metabolism, and parent compound and/or metabolites elimination in patients with renal insufficiency. Furthermore, in patients with end-stage renal disease treated by dialysis, drugs are likely to be removed by extracorporal epuration and dosage and/or interval modifications should thus be applied to treatments in those patients. CLINICAL ASSESSMENT: Pharmacokinetics of drugs should be evaluated in patients with renal failure to determine whereas dosage and/or administration interval should thus be modified to enhance tolerance and pharmacological efficacy. Such studies are obviously necessary for drugs that are mainly excreted unchanged in urine. They should also be performed for drugs that are mainly degraded in the liver with emphasis on metabolites pharmacokinetics.