Studies of the clinical pharmacology of anticancer drugs used to treat childood cancers focus on new drug development and on the design of more rational approaches to the use of these agents based on the study of their pharmacokinetics and pharmacodynamics. The central nervous system (CNS) pharmacology of anticancer drugs and the identification of new treatment approaches for CNS tumors are emphasized. An integrated research program, which includes preclinical models to study the pharmacology of novel agents and an active clinical trials program to study the toxicity, activity, and pharmacology of these agents in children, is utilized. The CNS pharmacology of anticancer drugs is studied in a non-human primate model with indwelling ventricular catheters that allow for drug instillation into the ventricle and sampling of the cerebrospinal fluid (CSF). Drug penetration into the CSF, which serves as a surrogate measure of blood-brain barrier (BBB) penetration, is used to identify potential new drugs for CNS tumors. Drug penetration into brain and other tissues is also measured using microdialysis. In addition, new strategies to pharmacologically modulate the BBB are being investigated in this model. The preclinical and clinical development of new agents that can be administered intrathecally for the treatment of meningeal tumors is also focus of research. Clinical trials are performed as single institution studies or collaboratively with other children's cancer centers or Children's Oncology Group. A variety of agents are studied, including classical cytotoxic drugs, drugs with novel mechanisms of action, and agents that modulate the effect of anticancer drugs. Novel clinical trial designs are developed to optimally study new agents in children. Clinical pharmacokinetic studies focus on the development of pharmacokinetic models that allow for simulation of other doses and schedules, development of limited sampling strategies to simplify drug monitoring, and correlation with pharmacodynamic parameters, such as toxicity or response. Pharmacokinetic studies are being performed on a number of adult clinical trials in collaboration with investigators in the Medicine and Surgery Branches. New approaches to imaging and monitoring response in CNS tumors utilizing nuclear magnetic resonance spectroscopy and 3-dimensional image analysis, are incorporated into clinical brain tumor trials.
Showing the most recent 10 out of 32 publications
