Thomas Storme

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination

BackgroundAntibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement.MethodsA sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis.ResultsIn 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics – gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin – covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5th minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations.ConclusionsThe current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Population pharmacokinetics and dosing optimization of vancomycin in children with malignant hematological disease

ABSTRACT An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had subtherapeutic steady-state trough concentrations (Css/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target Css/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population.

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.

Population pharmacokinetics and dosing optimization of teicoplanin in children with malignant haematological disease

AIM Children with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high risk population. METHODS The current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin were analyzed using nonmem software. The dosing regimen was optimized based on the final model. RESULTS Eighty-five children (age range 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n = 143) were available for analysis. With the current recommended dose of 10 mg kg(-1) day(-1) , 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min <10 mg l(-1) ). A two compartment pharmacokinetic model with first order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg l(-1)  h 18 mg kg(-1) was required for infants, 14 mg kg(-1) for children and 12 mg kg(-1) for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared with the mg kg(-1) basis dose, making the modelling approach an important tool for dosing individualization. CONCLUSIONS This first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.

European Study of Neonatal Exposure to Excipients: An update

APHP – Hospital Antoine Beclere, PharmacyDepartment, Paris, FranceE-mail address: UKmark.turner@liverpool.ac.uk(M.A. Turner).TheEuropeanStudyofNeonatalExposuretoExcipients(ENSEE)aimstoprovideanevidencebasefordiscussionsaboutthesafetyofexcipients in medicines given to newborn babies. Excipients havegeneratedalotofdiscussionbuttodatethisdiscussionhasnotbeensupportedbydata.Somepeopleadvocateanextremeapplicationofthe precautionary principle and suggest that all excipients shouldbe avoided. Others advocate a balanced approach which acceptsthe use of excipients if it is impossible to formulate a medicineotherwise.Somewouldevenacceptanexcipientthatincreasesthemarketability of a product if the excipient poses a negligible risk.In order to inform this discussion ESNEE is conducting multiplestrands of research to provide an integrated source of information.ESNEE relates to the FAO/WHO model for the risk assessmentof chemicals in food. This includes hazard identification, hazardcharacterization and exposure assessment. These steps inform riskcharacterization.Hazardidentificationandcharacterisationhasbeenundertakenusingasystematicreviewofextantdatarelatingtoexcipientsafetyand kinetics. Exposure assessment involves surveys of medicinesuse and clinical studies of excipient kinetics using micro samplesandpopulationpharmacokineticmodels.Riskcharacterisationwillbe expressed in monographs about specific excipients, which willinclude information relevant to risk managers.The systematic review was developed and conducted by col-leagues in Paris (Vaconsin et al., 2012). The starting point for thesystematic review is that excipients are widely used chemicalswithsynonymsthatfeatureinmanyprimarysourcesnotrelatedtoneonates. Accordingly a selection process was required. This wasdeveloped in collaboration with EuPFI (Salunke and Tuleu, 2010).A refined search sentence was developed to account for excipientterms and neonatal terms. The first review examined propyleneglycol.Theinitialsearchesyielded35,000hits.Inordertoovercomethe challenges presented by such a wide search several steps weretaken including database exploration, sieving, and data extraction.

GRP-001 1St ESNEE Excipient Monograph: Information Needed to Formulate, Prepare and Prescribe Medicines For Neonates Containing Propylene Glycol as an Excipient

Background Neonates are particularly vulnerable to the adverse effects of medicines and excipients because their organs are immature. ESNEE (European Study of Neonatal Exposure to Excipients) is a European research consortium created in 2011 after the PRIOMED-CHILD call for proposals. Purpose The aim of ESNEE workpackage 2 was to conduct a literature review of excipients used in medicines for neonates and to establish a monograph of information for each excipient. Materials and Methods A systematic review of the literature was conducted with 6 key databases (i.e. Medline, Web of Science, Pascal, International Pharmaceutical Abstracts, Biosis previews, Embase). Hits were selected for their relevance according to criteria set by toxicology experts. Summaries of relevant papers were prepared with underlying critical information in a table. A face to face meeting was organised with experts to validate the data. Experts from European Medicines Agency Paediatric Committee (EMA PDCO) were involved. Results The search strategy identified around 1500 papers of which 87 were relevant to our purpose. Among those papers, 17, 20, and 15 corresponded to non-clinical, case report, and epidemiological data respectively. The remaining 35 reported miscellaneous data observed in adults. The monograph includes some general information (chemical structure, pharmaceutical use), the list of all (propylene glycol) PG-containing medicines used in Europe for neonates collected by ESNEE workpackage 1 during a point prevalence study, the kinetic characteristics of PG, the first signs of toxicity (biological perturbation, clinical signs, etc.), the organ to target for monitoring and follow up for short or long term effects, some estimations of Acceptable Daily Intake (ADI), and Permitted Daily Exposure (PDE) and finally some recommendations to manage PG toxicity. Conclusions This is the first monograph on PG that includes the most available and relevant information validated by a panel of European experts. This documented, accurate and practical information should help the pharmaceutical industry and hospital pharmacists when formulating/preparing medicines and neonatologists when prescribing such PG-containing medicines. It also provides a clear image of which information is lacking and warrants further experimental investigation. No conflict of interest.