Modelling approaches to dose estimation in children

Abstract

Most of the drugs on the market are originally developed for adults and dosage selection is based on an optimal balance between clinical efficacy and safety. The aphorism 'children are not small adults' not only holds true for the selection of suitable drugs and dosages for use in children but also their susceptibility to adverse drug reactions. Since children may not be subject to dose escalation studies similar to those carried out in the adult population, some initial estimation of dose in paediatrics should be obtained via extrapolation approaches. However, following such an exercise, well-conducted PK-PD or PK studies will still be needed to determine the most appropriate doses for neonates, infants, children and adolescents.

Figure 1

Representative plot showing the combined effects of dose frequency and total daily dose on the overall 24-h reduction in plasma homocysteine concentration

Figure 2

Paediatric drug development decision tree for types of PK-PD studies required in children (Center for Drug Evaluation and Research)

Figure 3

Example of a whole body Physiologically based Pharmacokinetic model

Figure 4

Changes in caffeine CL_u (1a) and midazolam CL_u (1b) with body weight (predicted CL_u: median = solid line and 95% CI = dashed line; observed CL_u= ellipses)

Figure 5

Concordance between predicted & observed caffeine CL_u values (a) and midazolam CL_u values (b). Variability (±95% CI) is indicated by the height and width of the ellipses