The clinical pharmacology of antineoplastic agents used in the treatment of pediatric malignancies studied with emphasis on the role of pharmacologic monitoring and on both pre-clinical 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 Piritrexim, All-trans retinoic acid and Thiotepa plus GM-CSF are being completed. A major effort of this project is to investigate 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, intrathecal 6-MP, and intrathecal mafosfamide, all approaches developed in this model, are in progress. A clinical study evaluating continuous intra-CSF drug infusion via a unique indwelling drug delivery device also 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. The CNS pharmacology of antiretroviral therapies is being systematically evaluated in our non-human primate model, to determine which agents may be most effective against 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 patients treated on these trials.
