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Scaling Clearance in Paediatric Pharmacokinetics: all models are wrong, which are useful?

Germovsek, E; Barker, C; Sharland, M; Standing, JF; (2017) Scaling Clearance in Paediatric Pharmacokinetics: all models are wrong, which are useful? British Journal of Clinical Pharmacology , 83 pp. 777-790. 10.1111/bcp.13160. Green open access

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Abstract

AIM(S): When different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model-based meta-analysis. This study aimed to compare published models with the proposed standard (allometric weight(0.75) and sigmoidal maturation function). METHODS: A systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike Information Criteria (AIC) and visual predictive checks were used for evaluation. RESULTS: No model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters) -4.1(5), -9.2(4), -10.8(5) and -10.1(5) respectively. The 95%CI of estimated CL for all top performing models overlapped. CONCLUSIONS: No evidence to reject the standard model was found; given the benefits of standardised parameterisation, it's use should therefore be recommended.

Type: Article
Title: Scaling Clearance in Paediatric Pharmacokinetics: all models are wrong, which are useful?
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bcp.13160
Publisher version: http://dx.doi.org/10.1111/bcp.13160
Language: English
Additional information: © 2016 The Authors . British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Allometric scaling, NONMEM, allometric exponent, children, gentamicin, infants, maturation function, midazolam, neonates, pharmacometrics
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/1528688
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