Drug therapy in childhood: what has been done and what has to be done?

Abstract

Exactly 30 years ago the German pediatrician Dost introduced the concept of pharmacokinetics into clinical and experimental research. In the following years this concept prompted a rapidly increasing understanding of the mechanisms of drug disposition and of host factors as major determinants of drug concentration and, in consequence, of drug effect within the organism. This has led to a burgeoning new discipline--clinical pharmacology. However, the pharmacokinetic approach was, with few exceptions, not particularly cherished by the pediatricians, until dramatic clinical accidents, such as the chloramphenicol-gray syndrome and the thalidomide-phocomelia tragedies occurred, which highlighted the pharmacokinetic, and pharmacodynamic, features of the growing organism, especially of the fetus, newborn, and young infant. In the 1970s, the explosive development of sensitive and specific methods for the analysis of nearly all drugs in body fluids and tissues and the great progress in computer technology induced an enormous progress in clinical pharmacokinetics making age-related drug and dosage recommendations possible, which were based on scientific data, and initiating therapeutic drug monitoring. However, years ago, in 1965, von Harnack and others published pediatric drug dosage recommendations based on empiric data realizing that, for many drugs, an appropriate dosage schedule can be achieved when the drug dose is calculated according to body surface area rather than to body weight. While advances in pediatric pharmacokinetics have been proceeding at a rapid pace during the last decade, it is quite evident that the progress in pharmacodynamics has lagged far behind the research and attention paid to pharmacokinetics. For the future increasing work concerning the quantitation of clinical effects in correlation to drug dosage and drug level is urgently needed. That holds true for short-term and for long-term clinical effects of drugs given to newborns, infants, and children, as well as for adverse and for desired therapeutic effects of drugs administered to an unborn via his mother. Undoubtedly, quantitative determination of clinical drug effects is much more difficult than quantitation of pharmacokinetics, not only for technical, but also for ethical reasons. Moreover, pharmacodynamic studies in long-term treatment of chronically ill children are complicated by the problem of the patient's compliance. However, the rapid progress in pediatric oncology in the past is an impressive example for the usefulness of controlled clinical trials based on pharmacodynamic rather than pharmacokinetic criteria.