The PET Section studies the clinical pharmacology of the anticancer and antiretroviral drugs used in the treatment of children with cancer and HIV-infection. The primary focus of the section is on new drug development, although established drugs (anthracyclines, vinca alkaloids, antimetabolites, platinum analogs) are also investigated. An integrated approach incorporating preclinicaI studies in in vitro and animal models, as well as clinical trials and clinical pharmacokinetic studies, is utilized. For new systemic anti-cancer drugs, analytical techniques to assay drug concentrations are developed and preclinical pharmacokinetic studies are performed in a nonhuman primate model which is highly predictive of drug disposition in humans. In addition, cytotoxicity studies are performed in pediatric tumor cell lines to define cytotoxic concentrations, schedule dependence. and, with the establishment of a pediatric tumor cell line panel, the potential spectrum of activity of the new agent against pediatric tumors. These preclinical studies guide in the design of the initial phase I and II trials and pharmacokinetic studies in humans. The PET Section has performed or is conducting a significant proportion of the new agent studies in children nationally (topotecan, all-trans-retinoic acid, pyrazoloacridine, taxotere, intravenous thioguanine, carboxypeptidase, tomudex, taxol, prolonged infusions of etoposide). The section is also collaborating with other COP branches and has performed pharmacokinetic studies in adults treated with both investigational and standard agents (taxol, doxorubicin, fluorouracil). In addition to the development of new systemic agents, we have established a unique program to study the central nervous system pharmacology of new and existing anticancer drugs. Systemically administered drugs that penetrate well across the blood brain barrier are identified, and targeted for studies in patients with brain tumors (thiotepa, topotecan, temozolomide). We have also developed several new agents (diaziquone, mercaptopurine, mafosfamide, topotecan) that can be administered intrathecally for the treatment of meningeal relapse. The studies of existing agents are designed to identify more rational approaches to their use by developing limited sampling strategies to simplify drug monitoring and defining pharmacodynamic correlates that relate drug concentrations to toxicity or efficacy of the drug. The approach to the study of antiretroviral drugs in children parallels that of the anticancer drugs. Drug assays are developed, preclinical pharmacokinetic studies are performed in the animal model with an emphasis on defining the CNS pharmacology of the agent, and clinical pharmacokinetic/pharmacodynamic studies are performed in children treated on Pediatric Branch trials of new and existing antiretroviral drugs.
