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Population clinical pharmacology of children: modelling covariate effects

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Abstract

Introduction

Population modelling using mixed effects models provides a means to study variability in paediatric drug responses among individuals representative of those in whom the drug will be used clinically.

Discussions

Explanatory covariates explain the predictable part of the between-individual variability. Growth and development are two major aspects of children not seen in adults. These aspects can be investigated by using size and age as covariates. Problems attributable to co-linearity can be approached by using size as the first covariate. Size standardisation is achieved using allometric scaling, a mechanistic approach that has a strong theoretical and empirical basis. Age is used to describe the maturation of clearance. The quantitative models (linear, exponential, first-order, variable slope sigmoidal) used to describe this maturation process vary depending on the span of the ages under investigation. Measures of response are not always straightforward and can be more difficult to quantify in children.

Conclusion

Covariate investigation in children is improving the understanding of developmental aspects of drug disposition and effects in the paediatric population, ultimately leading to more effective use of medications.

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Abbreviations

BMR:

Basal metabolic rate

BSA:

Body surface area

CL:

Clearance

CLcr:

Creatinine clearance

CPR:

Creatinine production rate

GFR:

Glomerular filtration rate ka; absorption rate constant

ln:

Natural logarithm

NONMEM:

Nonlinear mixed effects model

PD:

Pharmacodynamics

PK:

Pharmacokinetics

PMA:

Postmenstrual age

PNA:

Postnatal age

PWR:

Allometric power exponent

Tabs:

Absorption half time

TDM:

Therapeutic drug monitoring

V:

Volume of distribution

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Acknowledgement

The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) by a Clinical Doctoral Grant (A 6/5–KV–G 1).

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Authors and Affiliations

  1. Department of Anaesthesiology, University of Auckland, Auckland, New Zealand

    Brian J. Anderson

  2. Neonatal Intensive Care Unit, University Hospital Gasthuisberg, Leuven, Belgium

    Karel Allegaert

  3. Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand

    Nicholas H. G. Holford

  4. C/- PICU, Auckland Children’s Hospital, Park Road, Auckland, New Zealand

    Brian J. Anderson

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  1. Brian J. Anderson
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Correspondence to Brian J. Anderson.

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Anderson, B.J., Allegaert, K. & Holford, N.H.G. Population clinical pharmacology of children: modelling covariate effects. Eur J Pediatr 165, 819–829 (2006). https://doi.org/10.1007/s00431-006-0189-x

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