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Development of a novel multi-penicillin assay and assessment of the impact of analyte degradation: lessons for scavenged sampling in antimicrobial pharmacokinetic study design.

Kipper, K; Barker, CIS; Standing, JF; Sharland, M; Johnston, A; (2018) Development of a novel multi-penicillin assay and assessment of the impact of analyte degradation: lessons for scavenged sampling in antimicrobial pharmacokinetic study design. Antimicrobial Agents and Chemotherapy , 62 (1) 10.1128/AAC.01540-17. Green open access

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Abstract

Penicillins are widely used to treat infections in children, however the evidence is continuing to evolve in defining optimal dosing. Modern paediatric pharmacokinetic study protocols frequently favour 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 modelling, to investigate the suitability of scavenged sampling strategies.Using a rapid ultra-high 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 modelling was evaluated.All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 hour remaining in the range of 98-103% of the original concentration. More rapid analyte degradation had already occurred after 4 hours 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 hours. Modelling 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 modelling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring.

Type: Article
Title: Development of a novel multi-penicillin assay and assessment of the impact of analyte degradation: lessons for scavenged sampling in antimicrobial pharmacokinetic study design.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1128/AAC.01540-17
Publisher version: http://doi.org/10.1128/AAC.01540-17
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10030794
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