dc.contributor.author | Kipper, K | en_US |
dc.contributor.author | Barker, CIS | en_US |
dc.contributor.author | Standing, JF | en_US |
dc.contributor.author | Sharland, M | en_US |
dc.contributor.author | Johnston, A | en_US |
dc.date.accessioned | 2017-11-21T11:54:14Z | |
dc.date.available | 2017-10-24 | en_US |
dc.date.issued | 2018-01 | en_US |
dc.date.submitted | 2017-11-09T10:12:15.036Z | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/28847 | |
dc.description.abstract | Penicillins are widely used to treat infections in children; however, the evidence is continuing to evolve in defining the optimal dosing. Modern pediatric pharmacokinetic study protocols frequently favor opportunistic, "scavenged" sampling. This study aimed to develop a small-volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modeling, to investigate the suitability of scavenged sampling strategies. Using a rapid ultrahigh-performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin, and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modeling was evaluated. All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 h, remaining in the range of 98 to 103% of the original concentration. More-rapid analyte degradation had already occurred after 4 h, with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 h. Modeling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance. Five common penicillins can now be measured in a single low-volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modeling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring. | en_US |
dc.description.sponsorship | The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° 608765. This work was also supported by PUTJD 22 from the Estonian Research Council. Charlotte I.S. Barker (CISB) was funded as a Clinical Research Fellow by the Global Research in Paediatrics (GRiP) Network of Excellence, part of the European Union’s Seventh Framework Programme for research, technological development and demonstration (FP7/2007–2013, grant agreement number 261060), which also funded the NAPPA study (EudraCT 2013-002366-40, NCT01975493)(24). Mike Sharland chairs the UK Department of Health expert Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection, is an independent scientific advisor to NICE (National Institute for Health and Care Excellence), and also receives institutional academic research grants from the NIHR (National Institute for Health Research) and the European Union. Joseph F. Standing (JFS) has received funding from United Kingdom Medical Research Council Fellowships (grants G1002305 and M008665). CISB and JFShave been supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Antimicrob Agents Chemother | en_US |
dc.subject | beta-lactams | en_US |
dc.subject | drug stability | en_US |
dc.subject | high-pressure liquid chromatography | en_US |
dc.subject | mass spectrometry | en_US |
dc.subject | penicillins | en_US |
dc.subject | pharmacokinetics | en_US |
dc.subject | scavenged sampling | en_US |
dc.title | Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design. | en_US |
dc.type | Article | |
dc.rights.holder | © American Society for Microbiology | |
dc.identifier.doi | 10.1128/AAC.01540-17 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29084754 | en_US |
pubs.issue | 1 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 62 | en_US |
dcterms.dateAccepted | 2017-10-24 | en_US |