What makes pharmacotherapy challenging in paediatrics?

From birth through adolescence, the body undergoes continuous growth and maturation. Organs develop at different speeds, and the systems that absorb, distribute, break down, and eliminate medicines are constantly changing.  In neonates, the stomach is less acidic, metabolism in the liver is immature, kidney function is reduced, have a higher total body water content and lower protein levels in the blood, compared to adults. During infancy, rapid maturation occurs. Liver enzymes and kidney function develop quickly, and body composition shifts from predominantly water to increasing fat and muscle. Drug clearance and distribution can change within months, requiring frequent dose adjustments. In children 2-12 years old, drug metabolism may even exceed adult levels when adjusted for body weight.  By adolescence, physiology approaches adult norms, but hormonal changes and growth-related variability still require careful individualization. 

As a result, traditional dosing strategies, which often rely on adult data, ignore the profound physiological changes during childhood that alter how drugs are absorbed, distributed, metabolized, and excreted. Failing to account for these changes can lead to sub-therapeutic exposure or toxicity. Simply scaling the dose by weight is often insufficient, as developmental stage, organ function, and genetic factors introduce variability. Therefore, when developing dosing recommendations for children, it is crucial to account for the dynamic process of maturation.

How do we understand and predict these exposure changes?

A rapidly emerging solution to understanding and predicting changes in drug exposure during childhood is the use of physiologically based pharmacokinetic (PBPK) modelling. PBPK modelling allows us to create a detailed virtual representation of the human body, simulating how a medicine is absorbed, distributed, metabolized, and eliminated. Our PBPK models are specifically adapted to reflect these age-related physiological changes, ensuring that the predictions we make are as accurate as possible for this unique population.

What is model-informed dosing in paediatrics?

Once a PBPK model has been built and verified, it can be used to predict drug exposure and prospectively explore alternative dosing strategies. We evaluate different dosing regimens (e.g. dose amount or time between doses), but also different age groups, since physiological changes continue throughout childhood. A dosing regimen is considered appropriate when it maintains drug levels within the therapeutic range; high enough to be effective, but low enough to avoid toxicity.

Model-informed dosing provides evidence to support dose selection. This is especially valuable in populations where clinical data are limited, such as paediatrics. Importantly, it does not replace clinical evidence. Final recommendations must also consider safety, effectiveness, and practical feasibility in the target population.

In Project Madam, we perform PBPK studies to evaluate current paediatric dosing strategies and provide new dosing proposals that meet efficacy targets, while avoiding excessive peak exposures, to inform clinical practice.