ABSTRACT
Children cannot be regarded as miniature adults in terms of drug response, due to differences in body constitution, drug absorption and elimination, and sensitivity to adverse reactions. Informed consent is problematic and commercial interest has been limited by the small size of the market, so clinical trials in children have lagged behind those in adults. Regulatory agencies in the USA and Europe now recognize this problem and are attempting to address it, for example, by introducing exclusivity legislation designed to attract commercial interest. Traditionally, paediatricians have used drugs ‘off-label’ (i.e. for unlicensed indications), often gaining experience in age groups close to those for which a product is licensed and then extending this to younger children. That this empirical approach has worked (at least to some extent) is testament to the biological fact that while not just ‘miniature adults’ children do share the same drug targets (e.g. receptors, enzymes), cellular transduction mechanisms and physiological processes with their parents. Drug responses are thus usually qualitatively similar in children and adults, although there are important exceptions, including some central nervous system (CNS) responses and immunological responses to ciclosporin. Furthermore, some adverse effects occur only during certain stages of development, for example, retrolental fibroplasia induced by excess oxygen in the premature neonate and staining of teeth by tetracycline which occurs only in developing enamel. The processes of drug elimination are, however, immature at birth so quantitative differences (e.g. in dose) are important. Establishing optimal doses for drugs prescribed for children is thus an extremely important clinical challenge. Current regimes have been arrived at empirically, but guidelines are evolving for paediatric dosing in clinical trials and in future greater use may be made of pharmacokinetic/pharmacodynamic modelling in children, so hopefully this Cinderella
of therapeutics will soon be making her (belated) entry to the ball.
