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 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. Additional efforts to optimize G-MP administration have been based on in vitro studies which have demonstrated a need for prolonged exposure to cytocidal concentrations of drug to maximize leukemic cell kill. Clinical Phase II protocols evaluating prolonged intravenous 6-MP infusions for acute leukemia, brain tumors and solid tumors are under way. Preclinical and clinical pharmacokinetic studies of a variety of new agents, such as Fazarabine and Piritrexim are in progress. A Phase I study of Thiotepa in pediatric patients has been completed which documents the excellent penetration of this agent into the CNS. 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. Clinical studies of intrathecal AZQ and continuous intrathecal 6MP are in progress. Pre-clinical studies evaluating intra-CSF drug administration via indwelling drug delivery devices is under way. This model has also been used to assess the CNS penetration of a variety of new antiretroviral agents (used to treat AIDS). Clinical pharmacologic support for ongoing Phase I trials in children with AIDS is also pursued in this section.
