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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 10/2006

01-10-2006 | Original Research Article

Development and Evaluation of a Generic Physiologically Based Pharmacokinetic Model for Children

Authors: Dr Andrea N. Edginton, Walter Schmitt, Stefan Willmann

Published in: Clinical Pharmacokinetics | Issue 10/2006

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Abstract

Background

Clinical trials in children are being encouraged by regulatory authorities in light of the immense off-label and unlicensed use of drugs in the paediatric population. The use of in silico techniques for pharmacokinetic prediction will aid in the development of paediatric clinical trials by guiding dosing regimens, ensuring efficient blood sampling times, maximising therapeutic effect and potentially reducing the number of children required for the study. The goal of this study was to extend an existing physiologically based pharmacokinetic (PBPK) model for adults to reflect the age-related physiological changes in children from birth to 18 years of age and, in conjunction with a previously developed age-specific clearance model, to evaluate the accuracy of the paediatric PBPK model to predict paediatric plasma profiles.

Methods

The age-dependence of bodyweight, height, organ weights, blood flows, interstitial space and vascular space were taken from the literature. Physiological parameters that were used in the PBPK model were checked against literature values to ensure consistency. These included cardiac output, portal vein flow, extracellular water, total body water, lipid and protein. Five model compounds (paracetamol [acetaminophen], alfentanil, morphine, theophylline and levofloxacin) were then examined by gathering the plasma concentration-time profiles, volumes of distribution and elimination half-lives from different ages of children and adults. First, the adult data were used to ensure accurate prediction of pharmacokinetic profiles. The model was then scaled to the specific age of children in the study, including the scaling of clearance, and the generated plasma concentration profiles, volumes of distribution and elimination half-lives were compared with literature values.

Results

Physiological scaling produced highly age-dependent cardiac output, portal vein flow, extracellular water, total body water, lipid and protein values that well represented literature data. The pharmacokinetic profiles in children for the five compounds were well predicted and the trends associated with age were evident. Thus, young neonates had plasma concentrations greater than the adults and older children had concentrations less than the adults. Eighty-three percent, 97% and 87% of the predicted plasma concentrations, volumes of distribution and elimination half-lives, respectively, were within 50% of the study reported values. There was no age-dependent bias for term neonates to 18 years of age when examining volumes of distribution and elimination half-lives.

Conclusion

This study suggests that the developed paediatric PBPK model can be used to scale pharmacokinetics from adults. The accurate prediction of pharmacokinetic parameters in children will aid in the development of dosing regimens and sampling times, thus increasing the efficiency of paediatric clinical trials.
Footnotes
1
The use of trade names is for product identification purposes only and does not imply endorsement.
 
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Metadata
Title
Development and Evaluation of a Generic Physiologically Based Pharmacokinetic Model for Children
Authors
Dr Andrea N. Edginton
Walter Schmitt
Stefan Willmann
Publication date
01-10-2006
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 10/2006
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/00003088-200645100-00005

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