Georgi Nellis

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.

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.

Potentially harmful excipients in neonatal medicines: a pan-European observational study

Objectives We aimed to describe administration of eight potentially harmful excipients of interest (EOI)—parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride—to hospitalised neonates in Europe and to identify risk factors for exposure. Methods All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis. Results Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient. Conclusions European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients.

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.

Comparison of two alternative study designs in assessment of medicines utilisation in neonates

BackgroundEstimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use.MethodsA Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected.To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation.ResultsOf 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R2 = 0.93).ConclusionThe simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates.

Age-Appropriate Formulations Including Pharmaceutical Excipients in Neonatal Medicines

BACKGROUND The development of appropriate pharmaceutical formulations for routine neonatal practice is challenging because of the developmental characteristics and the need for it to be specifically ageappropriate. This has led to wide use of extemporaneous formulations, which lack standardized procedures that can result in medication errors in clinical practice resulting in suboptimal efficacy and safety concerns. METHODS We have reviewed the most recent literature on formulations and pharmaceutical excipients. RESULTS We present the issues related with the lack of age-appropriate formulations, discuss the importance and extent of exposure to pharmaceutical excipients known to be harmful to neonates, indicate ways that can reduce exposure to excipients of concern, and review challenges of the design of age-appropriate drug formulations and dosage forms/drug delivery systems for neonates. Finally, we summarize novel approaches regarding drug delivery for neonates. CONCLUSION Novel approaches in age-appropriate drug delivery should overcome the present obstacles and improve the quality of medicines, thus avoiding errors in treatment and improving the management of neonates. Further basic researches on discovering new technologies and modern formulations, using in vitro testing systems as well as preclinical and clinical trials, are needed to improve the feasibility, practicality and safety of new formulations, including research on pharmaceutical excipients.

MEDICATION USE IN NEONATAL INTENSIVE CARE UNITS ACROSS EUROPE

Objectives This is the first Europe-wide study aiming to describe the medication use in Neonatal Intensive Care Units and to analyse the factors that might influence the prescription pattern. Methods A pan-European one day point-prevalence study was conducted in 2012 where all of the prescriptions for hospitalised neonates were recorded. A trade name, manufacturer, active pharmaceutical ingredients (API), strength, galenic form and route of administration were registered. Results Altogether 2173 prescriptions were administered to 726 neonates from 21 countries, of whom 66% (477/726) were preterm, 12% (84/726) extremely preterm. There was inverse correlation between gestational age (GA) and median number of prescriptions per neonate (group median 2/IQR 1–4, extremely preterm 4/3–6, very preterm 3/2–5, late preterm 2/1–3, full-term 2/1–3). Median number of prescriptions per neonate was highest in the eastern region, among extremely preterm neonates (median=6.5/IQR 6–8.5). Highest prescription rate was for alimentary medicines (93/per 100 admissions), systemic antiinfectives (79/100) and medicines for blood (71/100). Antiinfectives were most frequently prescribed in the southern region (103/100). Multivitamins were most frequently used medications in most regions (western 74, southern 31, northern 31/100), except in eastern region (5/100). Most commonly prescribed API-s were multivitamins (32/100), caffeine (19/100), gentamicin (18/100), amino acids (18/100) and colecalciferol (15/100). Most frequently prescribed medications among extremely preterm neonates were caffeine (60/100), among very preterms multivitamins and caffeine (45 and 43/100), among late preterms multivitamins (44/100) and among full-terms phytomenadione (26/100) and gentamicin (24/100). Conclusions Our study revealed the most commonly used medications in neonates. Higher prescription rate among preterm neonates calls for further analysis of the suitability and safety of medications for infants with lower GA.

O-106 Populationpharmacokinetic Model Of The Antimicrobial Excipient Methyl Paraben Administered In Routine Clinical Practice To Neonates

Introduction Parabens are widely used as antimicrobial preservatives in medicines given to neonates. Some concerns have been raised about the potential of paraben toxicity. To date there have been no studies of the circulating concentrations of methyl paraben (MPB) in babies. This study aimed to describe the relationship between dose of MPB administered and circulating concentrations using a population pharmacokinetic model. Methods Neonates in 4 UK and 1 Estonian neonatal units who were prescribed paraben-containing medications were recruited with parental consent. Parabens were assayed in timed, dried blood spots using LCMSMS. The limit of quantification was 20ng/mL. Results 180 babies provided 841 samples of which 382 (45%) were below the limit of quantification. The mean (range) of observed blood MPB concentrations was 28.4 (10–874) ng/ml. The final kinetic model for MPB included first order absorption and two compartment disposition. Clearance was related to postnatal age (PNA). The model parameters are shown in the Table. Discussion Routine use of MPB as an excipient in medicinal formulations does not lead to markedly high circulating blood concentrations of MPB in neonates. We cannot exclude accumulation from these data. These findings will contribute to safety assessments and regulatory advice and may indicate that current levels of MPB in formulations are acceptable for young children. Abstract O-106 Table 1 Parameter Estimate % Relative Standard Error Clearance if PNA <21 days (L/hr) 0.57 9.57 Clearance if PNA ≥21 days (L/hr) 0.88 7.19 Central volume (L/1.6kg) 1.84 7.55 Peripheral Volume (L) 12.2 12.0 Residual (proportionate) Error (%) 44.5 4.7