The change from treating children and neonates as little adults has occurred gradually. Previously size and gestational age were viewed as the main determinants of drug clearance, but this has been replaced with the view that the capacity and functions of individual organs and the development of biochemical pathways are of greater importance.9 The development of drug metabolism and clearance pathways begins in the fetus and continues throughout childhood.12 A study by the FDA examined different methods of predicting paediatric clearance of drugs based on adult values, and concluded that no single method of prediction is suitable for all drugs or age groups.4
Dosage regimens based entirely on age are often inaccurate and may lead to adverse effects, toxicity or lack of clinical effect. There is a lack of pharmacokinetic studies in children of different ages.
Dosing information is difficult to determine in children as traditional pharmacokinetic studies are hard to conduct in children and are subject to a greater range of ethical considerations. These studies require large amounts of blood to be taken over periods of time and this is not considered ethical in children. The development of population pharmacokinetic modelling has allowed paediatric-specific dosing information to be developed.13 These new techniques will assist in developing safer dosing information for children over time by reducing the burden of pharmacokinetic studies. Although improving, no mathematical method of dose estimation can replace clinical studies using actual outcomes, surrogate measures or therapeutic drug monitoring.14
Weight-based and surface-area-based dosing regimens are simple and are used in most clinical situations. However, with the lack of specific paediatric data, these dosing equations are often based on adult data and then scaled based on size and age as an approximation for drug activity in children. Paediatric growth and development is not a linear process. Scaling from adult doses based on weight alone is not adequate for determining doses across the range of developmental processes that occur throughout childhood.7 While this method may have some value in older children and adolescents, who have similar values to adults for body composition and organ function, it lacks utility in toddlers and neonates.
Therapeutic drug monitoring in conjunction with clinical review can be used to assess effectiveness and safety, but only when information about the safe and effective concentrations in children is available. Even for vancomycin, for which therapeutic drug monitoring is commonly performed, this information is not available.15 More information is available regarding the safe and effective concentrations of antiepileptic drugs in children, although therapeutic drug monitoring cannot predict all adverse effects, such as hepatotoxicity with sodium valproate.