of-body-weight basis) of anticonvulsants to achieve therapeutic levels. In contrast, infants and children may be at greater risk from other drugs and chemicals that undergo metabolic activation (i.e., conversion to bioactive or cytotoxic metabolites). Unfortunately, there is lack of information on such agents in humans in the published literature.
There was concern that acetaminophen (Tylenol), a drug that undergoes metabolic activation to hepatocytotoxic metabolite(s) via a P-450-mediated mixed-function oxidase (MFO) pathway, would cause increased morbidity and mortality in young children. This concern was never realized, however, since hepatotoxicity in young children was found to be less severe than in adults, and has rarely (Rumack, 1984). Acetaminophen is metabolized by several parallel pathways. The two major detoxification pathways involve conjugation of the parent compound with sulfate or glucuronide. Thus only a small fraction of the drug remains to be oxidized by the P-450-mediated pathway to a reactive intermediate (N-acetyl-p-benzoquinonimine). This metabolite is conjugated with glutathione to produce nontoxic products or can bind covalently to cell proteins and nucleic acids, causing cellular injury (Hinson et al., 1990). Although prepubescent children have relatively high hepatic MFO activity, they also exhibit a greater capacity than adults to detoxify acetaminophen by phase II metabolic reactions, primarily sulfate conjugation (Miller et al., 1977). Also, higher glutathione levels in the young may contribute to protection from hepatotoxicity. Thus, the lower susceptibility of children to acetaminophen poisoning is due to their greater capacity to eliminate the drug by nontoxic pathways (Kauffman, 1992).
Clinical trials in infants and children are relatively infrequent for most classes of drugs, but this is not the case for many antineoplastic agents. Although some types of childhood cancer are refractory to chemotheraphy, others have excellent cure rates (Petros and Evans, 1992). Therefore, phase I clinical trials are frequently conducted in both adult and pediatric populations to define the maximum tolerated dose (MTD) for appropriate dosage schedules in phase II trials. Antineoplastic agents include a wide variety of different types of chemicals that act by diverse mechanisms. Thus, results of phase I studies of anticancer drugs afford scientists some of the most comprehensive data sets for contrasting toxic effects of chemicals in children and adults. The investigations typically involve repetitive dosage regimens lasting days or weeks, however, rather than single, acute exposures.
Comparable clinical trials of antineoplastic agents in pediatric and adult patient populations have revealed toxic effects that are often similar qualitatively but different quantitatively (Glaubiger et al., 1982; Marsoni et al., 1985; Evans et al., 1989). In compilation of data on 16 compounds for which there had been comparable phase I trials in adults and children,