European study of Neonatal exposure to Excipients (ESNEE)/Priomedchild Call/ERA-Net

Lead Research Organisation: University of Liverpool

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Excipents are chemicals added to medicines to improve their quality. Sporadic reports indicate that some may be toxic for neonates and lead to significant morbidity or death. However, there is insufficient information about the risks generated by excipient exposure because systematic surveys have not been done and studies on babies have not been ethical in the past. Recent advances allow determination of excipient levels in very small blood volumes (50 microlitre) including dry blood spot methods and estimates of excipient exposures based on only 2-4 samples per baby. Hypothesis 1: information about exposures across the EU will promote reduction of neonatal exposure to excipients by highlighting opportunities for product substitution and priorities for reformulation.|Hypothesis 2: small volume blood samples can be used to generate models of systemic excipient exposure. Our consortium comprises researchers from Estonia, France and the UK with extensive experience in all aspects of the study. We will develop a platform of techniques to assess excipient exposure including: a questionnaire and point prevalence study of neonatal excipient exposure; systematic reviews of relevant literature; dried blood spot assays for high impact excipients; a cohort study to construct population excipient kinetic models (EK, analogous to active drug pharmacokinetics or PK) for high impact excipients. This work will lead to recommendations for the European Medicines Agency and other stakeholders about assessment of excipient exposure and underpin future work to relate exposures to outcomes.|

Publications

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Nellis G (2012) Potentially Harmful Excipients in Antibiotics Prescribed to European Neonates - ESNEE Survey in Acta M├ędica Portuguesa : 3rd International Congress of UENPS

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Nellis G (2012) Medicines used for neonates in Europe - the survey of the European study of neonatal exposure to excipients (ESNEE). in Journal of Neonatal-Perinatal Medicine: 20th European Workshop on Neonatology

 
Description Citation in guidance document by European Medicines Agency
Geographic Reach Europe 
Policy Influence Type Citation in other policy documents
Impact Our data contributed to the risk-benefit analysis of commonly used excipients. Our findings confirmed in human neonates the suggestions from other sources that parabens are present at low concentrations following administration in existing medicines. The overall package of information supports the continued use of these excipients and avoids the need for costly reformulation of widely used medicines.
URL http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/11/WC500196733.pdf
 
Description EMA Advice
Geographic Reach Asia 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact Summary data from the clinical studies in the project have been shared with the European Medicines Agency. We are told that this has informed their position on the risks associated with parabens in newborn babies. Their guidance is still in draft
 
Description Interaction with European Medicines Agency
Geographic Reach Europe 
Policy Influence Type Membership of a guidance committee
 
Title Assay development 
Description Assays for parabens in whole blood samples collected in dried blood spots have been developed by the Pharmacy Dept at Queens University Belfast 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Assays are currently being applied to 500 samples from 150 babies recruited in our clinical studies 
 
Title Assay development, ethanol 
Description The Pharmacy Department at Leicester have developed an assay for ethanol and 3 of its metabolites from microsamples of plasma (50 micro litres) 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This assay is being applied to 150 samples from 50 babies recruited to the clinical study. 
 
Description Belfast 
Organisation Queen's University Belfast
Department School of Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution Clinical trials expertise; project management
Collaborator Contribution Assay expertise
Impact Not yet
Start Year 2009
 
Description Leicester 
Organisation University of Leicester
Department Leicester Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in clinical trials; project management
Collaborator Contribution Pharmacokinetic expertise, review of clinical materials
Impact Not yet
Start Year 2010
 
Description Paris 
Organisation Robert Debre Hospital
Country France 
Sector Hospitals 
PI Contribution Clinical trials expertise; project management
Collaborator Contribution Expertise in literature review
Impact Not yet
Start Year 2010
 
Description Paris 2 
Organisation Antoine Beclere Hospital
Department Pharmacy Antoine Beclere Hospital
Country France 
Sector Hospitals 
PI Contribution Clinical trials expertise; project management
Collaborator Contribution Pharmacy expertise
Impact Not yet
Start Year 2010
 
Description Tartu 
Organisation University of Tartu
Department Department of Paediatrics
Country Finland 
Sector Hospitals 
PI Contribution Clinical trials expertise; project management
Collaborator Contribution Survey expertise
Impact Not yet
Start Year 2010
 
Title Clinical study of excipient kinetics 
Description Excipients are widely used in medicines given to neonates but their circulating concentrations have never been evaluated. 
Type Management of Diseases and Conditions
Year Development Stage Completed 2013
Development Status Closed
Clinical Trial? Yes
UKCRN/ISCTN Identifier ISRCTN 31837223
Impact Our study of excipient kinetics examined three excipients. This is the first time this has been done in neonates. The use of dried blood spots was novel. The results have been published and presented to the regulatory authorities. 
URL http://www.isrctn.com/ISRCTN31837223
 
Description 21st European Neonatology workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Towards a systematic approach to risk assessment in neonates: a case study from the european study of neonatal exposure to excipients

Profile of study raised
Year(s) Of Engagement Activity 2013
 
Description Belfast presentation USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact S. Yakkundi 2013. Application of LC-MS/MS to Determine the Exposure to Methyl and Propyl Parabens in Preterm Neonates using Dried Blood Spot (DBS)",61ST ASMS Conference on Mass Spectrometry and Allied Topics, Minneapolis, USA, June 2013

Raising profile of study
Year(s) Of Engagement Activity 2013
 
Description CI poster ESPR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact M.A. Turner, S. Yakkundi, T. Metsvah, H.Varendi, G. Nellis, J.Windrow, S.Graham, H.Mulla, H.Pandya, S.Tapscott, N.Caldwell, J.Duncan, I.Lutsar, T.Nunn, J.McElnay 2013. Methyl and propyl paraben concentrations in preterm neonates exposed to clincially indicated medicines fall within safety margins for oestrogenic effects of these anti-microbial excipients. 54th Annual meeting ESPR, Oct 10-14, 2013, Portugal

Findings from study with regards to safety margins of methyl & propyl concentrations in neonates
Year(s) Of Engagement Activity 2013
 
Description Dried Blood Spots Editorial 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact An editorial about the use of dried blood spots to study experient kinetics in neonates was published in December 2011 .

Since this publication, there has been a lot of interest in the DBS excipient work. A couple of groups in the US and Mexico got in touch in order to discuss the paraben work.
Year(s) Of Engagement Activity 2011
 
Description ESNEE - Estonian presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Nellis, G.; Varendi, H.; Metsvaht, T.; Lutsar, I. (2012). Medicines used for neonates in Europe - the survey of the European study of neonatal exposure to excipients (ESNEE). In: Journal of Neonatal-Perinatal Medicine: 20th European Workshop on Neonatology, Tallinn, 27th - 30th June, 2012. IOS Press, 2012, (5; 2), 199.

Discussion arose around the subject area & study
Year(s) Of Engagement Activity 2012
 
Description ESPID Estonia presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Metsvaht, T.; Nellis, G.; Varendi, H.; Graham, S.; Rieutord, A.; Storme, T.; Vaconsin, P.; Nunn, AJ.; McElnay, J.; Millership, J.; Yakkundi, S.; Mulla, H.; Pandya, H.; Turner, MA.; Lutsar, I. (2013). DOSING OF FREQUENTLY USED ANTIBIOTICS IN EUROPEAN NICUS: POINT PREVALENCE STUDY OF EUROPEAN STUDY OF NEONATAL EXPOSURE TO EXCIPENTS (ESNEE). In: 31th Annual Meeting of ESPID (European Society of Pediatric Infectious Diseases); Milan; 28.05.-01.06.2013

Raising profile
Year(s) Of Engagement Activity 2013
 
Description Estonia Presentation blood concs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Nellis, G.; Lutsar, I.; Varendi, H.; Turner, MA.; Graham, S.; Rieutord, A.; Storme, T.; Vaconsin, P.; Nunn, AJ.; McElnay, J.; Millership, J.; Yakkundi, S.; Mulla, H.; Pandya, H.; Metsvaht, T. (2013). BLOOD CONCENTRATIONS OF METHYL AND PROPYL PARABENS IN NEONATES TREATED WITH GENTAMICIN AS THE MOST COMMONLY USED ANTIBIOTIC. 31th Annual meeting of ESPID (European Society of Pediatric Infectious Diseases) Milan, Italy; 28.05.-01.06.2013.

Raising profile of study
Year(s) Of Engagement Activity 2013
 
Description Ethanol Concentrations poster 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Presentation at the 14th ESDPPP Congress, Salzburg 2013. M.Hubbard, R.Cordell, H.Pandya, P.Monks, M.A.Turner, H.Mulla. Circulating ethanol concentrations in neonates administered clinically indicicated medications: feasibility of microsampling methods as part of the european study of neonatal excipient exposure.

Raising profile of study specifically with regards to ethanol sampling
Year(s) Of Engagement Activity 2013
 
Description Journal Article with Estonian Team 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Publication of Hospitalised neonates in Estonia commonly receiving potentially harmful excipients in the BMC Pediatrics Journal

The publication raised the profile of the ESNEE study in Estonia and resulted in sites expressing a wish to take part in the project
Year(s) Of Engagement Activity 2012
 
Description Journal Article with French Team 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Publication of ESNEE in the European Journal of Hospital Pharmacy to raise the profile of the ESNEE study throughout the European pharmacy community

The profile of the study was raised throughout Europe with many interested countries wishing to find out more information and to take part
Year(s) Of Engagement Activity 2012
 
Description Magazine article (Infant) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Magazine article targeted at health care professionals who would support clinical aspects of the project

Several new centres expressed an interest in participation, these centres are not part of our informal network of contacts
Year(s) Of Engagement Activity 2011
 
Description Nellis Poster Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Antibiotic prescribing in European neonatal intensive care units: Service Evaluation Survey of the European Study of Neonatal Exposure to Excipients poster presentation at the 30th meeting of ESPID. The poster was read by other professionals and led to discussion of the project and work carried out

Interest in the study rose
Year(s) Of Engagement Activity 2012
 
Description Nellis Presentation UENPS 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Abstract (Potentially harmful excipient in antibiotics prescribed to European neonates - ESNEE survey) accepted at the 3rd international congress of UENPS. Nellis G et al. Oral Presentation

Raising profile of the study
Year(s) Of Engagement Activity 2012
 
Description Poster Presentation (Belfast Team) (DBS to study excipient kinetics in neonates) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Health professionals
Results and Impact An ESNEE poster regarding the Dried Blood Sports (DBS) analysis of excipients at the Reid Bioanalytical Forum, Guildford, 2011. The poster created a lot of interest as this is the first of its kind in DBS area.

The impact was that the ESNEE team were asked to submit an editorial for the Journal
Year(s) Of Engagement Activity 2011
 
Description Potentially harmful excipients in antibiotics - Estonia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Potentially harmful excipients in antibiotics prescribed to european neonates - ESNEE survey. In: Acta Médica Portuguesa : 3rd International Congress of UENPS, 2012; Porto, nov 14-17. , 2012, (25; 2), 141. Nellis, Georgi; Varendi, Heili; Lass, Jana; Lutsar, Irja; Metsvaht, Tuuli

Discussion arose with regards to the presentation
Year(s) Of Engagement Activity 2012
 
Description Potentially harmful excipients in medicines - PPS - Estonia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Nellis, G.; Lutsar, I.; Varendi, H.; Lass, J.; Turner, MT; Metsvaht, T. (2013). Potentially harmful excipients in medicines prescribed to European neonates - ESNEE PPS. 54th Annual Meeting of European Society of Paediatric Research, Porto, Oct 10-14, 2013.

Raising profile of study
Year(s) Of Engagement Activity 2013
 
Description Probiotic use PPS - Estonia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Metsvaht, T.; Moor, R.; Nellis, G.; Varendi, H.; Lutsar, I. (2013). PROBIOTIC (PB) USE IN RELATION TO ANTIBIOTIC (AB) USE IN EUROPEAN NEONATAL INTENSIVE CARE UNITS (NICU): SUB-ANALYSIS OF ESNEE POINT PREVALENCE STUDY (PPS). 8th World Congress of the World Society for Pediatric Infectious Diseases; Capetown, South Africa; 20.-23. November 2013.

Raising profile of study
Year(s) Of Engagement Activity 2013
 
Description Probiotics Estonian presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Moor, R.; Metsvaht, T; Nellis, G.; Varendi, H.; Lutsar, I. (2013). The use of probiotics in European neonatal intensive care units: sub-analysis of the ESNEE point prevalence study. 2nd Baltic Pediatric Congress; Pärnu 30.05.-01.06.2013.

Raised discussion about the work carried out for project
Year(s) Of Engagement Activity 2013
 
Description Turner Poster 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Turner MA, Yakkundi S, Varendi H, Metsvaht T, Nellis G, Windrow J, Graham S, Mulla H, Pandya H, Tapscott S, Caldwell N, Duncan J, Lutsar I, McElnay J (2003). Methyl and propyl paraben concentrations in blood form preterm neonates exposed to clinically indicated medicines are lower than the concentrations of these anti-microbial excipients reported to affect cell physiology.

raising profile of study
Year(s) Of Engagement Activity 2013
 
Description Uni of Tartu presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Nellis G, Metsvaht T, Varendi H, Lass J, Turner M, Lutsar I
European study of neonatal excipient exposure (ESNEE): Preliminary results of the Point Prevalence Survey

Raising study profile
Year(s) Of Engagement Activity 2013