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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 3/2017

Open Access 01-03-2017 | Original Research Article

Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?

Authors: Elisa A. M. Calvier, Elke H. J. Krekels, Pyry A. J. Välitalo, Amin Rostami-Hodjegan, Dick Tibboel, Meindert Danhof, Catherijne A. J. Knibbe

Published in: Clinical Pharmacokinetics | Issue 3/2017

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Abstract

Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of ‘true’ paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated ‘true’ paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on ‘true’ CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age.
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Metadata
Title
Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?
Authors
Elisa A. M. Calvier
Elke H. J. Krekels
Pyry A. J. Välitalo
Amin Rostami-Hodjegan
Dick Tibboel
Meindert Danhof
Catherijne A. J. Knibbe
Publication date
01-03-2017
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 3/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0436-x

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