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The European Regulation on Better Medicines for Children1 requires companies that wish to develop a drug for use in Europe to agree a paediatric investigation plan (PIP) if the drug may have an indication for use in children. This very important legislation means that many more drugs will be investigated in children. New methodologies will be required to enable appropriate evaluation of drugs at all ages. Defining the optimal dose of a drug is one of the most difficult parts of the development process. Standard pharmacokinetic/pharmacodynamic (PK/PD) approaches, such as those used in phase I trials of healthy adults, involve administering either single or multiple doses of a drug to a small group of study participants. Blood samples are taken from participants at specified time intervals, based on absorption and distribution half-lives, and subsequently assayed for concentrations of drug and relevant metabolites. These data are pharmacokinetic parameters, and the effect of the drug at different concentrations can be assessed in pharmacodynamic studies.2 These approaches, if used for all new drugs in children of each relevant age group, present practical and ethical challenges. There are alternative methods, which may enable estimation of the optimal dose or dose range in a paediatric population. These methods include allometric scaling, a population pharmacokinetic (PK) approach, and in silico modelling.
Scaling is a common tool used to extrapolate within species at different ages and between animals and humans, although the factor used to scale the dose varies. Body weight is the easiest to use, but there is a non-linear relationship between weight and dose, and it has been known for more than 60 years that smaller species are generally more tolerant of drug treatment than larger species.3 Body surface area (BSA) was subsequently proposed to be a more satisfactory index of drug …