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Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

Germovsek, E; Barker, CIS; Sharland, M; Standing, JF (2017) Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful? Br J Clin Pharmacol, 83 (4). pp. 777-790. ISSN 1365-2125 https://doi.org/10.1111/bcp.13160
SGUL Authors: Sharland, Michael Roy Barker, Charlotte Ida Sophia

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Abstract

AIM: 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-analyses. This study aimed to compare published models with the proposed standard model (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% confidence interval of estimated CL for all top performing models overlapped. CONCLUSION: No evidence to reject the standard model was found; given the benefits of standardised parameterisation, its use should therefore be recommended.

Item Type: Article
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: NONMEM, allometric exponent, allometric scaling, children, gentamicin, infants, maturation function, midazolam, neonates, pharmacometrics, Allometric scaling, NONMEM, allometric exponent, children, gentamicin, infants, maturation function, midazolam, neonates, pharmacometrics, Pharmacology & Pharmacy, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Br J Clin Pharmacol
ISSN: 1365-2125
Language: eng
Dates:
DateEvent
21 October 2016Published Online
15 October 2016Accepted
13 March 2017Published
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
242146Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
SP4650 GN1834Action Medical Researchhttp://dx.doi.org/10.13039/501100000317
FP7/2007-2013 261060Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
G1002305Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
M008665Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 27767204
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/108365
Publisher's version: https://doi.org/10.1111/bcp.13160

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