The clinical pharmacology of antineoplastic agents used in the treatment of pediatric malignancies is studied with emphasis on the role of pharmacologic monitoring and on both preclinical and clinical pharmacologic studies of Phase I agents. The clinical pharmacology of orally administered antileukemic agents has been evaluated and the limited bioavailability and variable drug levels of 6-MP achieved following oral administration has been documented. Studies are underway to determine the extent to which this phenomenon is the cause of treatment failure. Preclinical and clinical pharmacokinetic studies of a variety of new agents including Fazarabine, Piritrexim, and Thiotepa plus GM-CSF are in progress. A major effort of this project is to study experimental approaches to the treatment of CNS malignancy. A unique primate model is utilized to study the CNS pharmacokinetics of various intrathecally and intravenously administered chemotherapeutic agents; to evaluate the neurotoxicities of various CNS treatments; and to evaluate and screen newer CNS treatment modalities and drug schedules. Information gained from the studies with this model is then applied to the design of clinical treatment protocols. Protocols evaluating strategies such as prolonged intravenous 6-MP infusions and intravenous Thiotepa for brain tumors are under way. Clinical studies of intrathecal AZQ and continuous intrathecal 6-MP, approaches developed in this model, are in progress. Preclinical studies evaluating intra-CSF drug administration via indwelling drug delivery devices is under way. As part of the Pediatric Branch AIDS research effort, the Leukemia Biology Section is studying the clinical pharmacology of antiretroviral agents in children. The study of these agents is a natural extension of our work on the clinical pharmacology of anticancer drugs, since most of the antiretroviral agents are nucleoside analogs, similar to the antimetabolites used in the treatment of ALL. We have focused on several areas of research. An in vitro model utilizing a human CD4 positive cell line has been established to study the biochemical pharmacology of the dideoxynucleosides which are prodrugs that require intracellular activation to their corresponding triphosphorylated nucleotide. The CNS pharmacology of the antiretroviral is being systematically evaluated in our nonhuman primate model, to determine which agents may be most effective against the CNS HIV infection. We have also participated in the design of clinical trials of antiretroviral agents in children and performed detailed pharmacokinetic studies in the children treated on these trials.
