Pharmacokinetic studies in paediatric patients. Clinical and ethical considerations

Important advances in paediatric clinical pharmacology have been made over the past 2 decades. However, there remains a reluctance to pursue pharmacodynamic and pharmacokinetic studies in children and, consequently, many important therapeutic agents have not been adequately studied in this population. Age-related pharmacokinetic/pharmacodynamic studies are not only essential to provide optimal drug therapy for children, but are quite feasible. Usually, paediatric pharmacokinetic studies are conducted in children receiving treatment for a specific medical condition. The approach to soliciting participation of paediatric subjects requires special sensitivity to the fears and anxieties of the child and the parents. Factors influencing subject enrollment and suggestions to enhance enrollment into study protocols are discussed. Pharmacokinetic/pharmacodynamic studies require repeated measurements over time and often entail obtaining multiple blood and urine samples. Techniques for reducing sample volume and number of necessary samples while minimising the discomfort and fear associated with obtaining multiple samples include the development of highly sensitive analytical methods to measure drug concentrations in small volume samples. The number of samples obtained from individual subjects can be minimised by using pharmacokinetic analytical approaches such as the nonlinear mixed effect model (NONMEM) which allows estimation of pharmacokinetic characteristics of a population using limited data from each subject. In addition, less invasive methods to measure drug metabolism/elimination such as salivary sampling, transcutaneous collection and breath analysis have been applied to the study of certain drugs. Children are a particularly vulnerable population because of their limited cognitive abilities and dependence on adults. Thus, they must be afforded greater protection from exploitation as research subjects than that provided to adults.