Clinical trials of new agents are studied separately in children because of potential differences in drug disposition and sensitivity to the effects of the drug compared to adults. Therefore, pharmacokinetic and pharmacodynamic studies are an important component of the early phase clinical trials performed in this population. Phase 1 trials performed by the Section include correlative studies to assess the pharmacokinetics of the new agent over a broad age range, and the results of these PK studies are compared directly with adult data and correlated with laboratory and clinical measures of drug effect. The Section has developed new trial designs that have incorporated pharmacologically based endpoints rather than toxicity to determine the optimal dose of new agent s in children. The pharmacokinetics and pharmacodynamics of new agents are also studied in preclinical models. The Section is studying the use of microdialysis as a tool to measure drug exposure in tumors, normal tissues and the blood with plans to extend this technology to patients receiving anticancer drugs. The PET Section provides pharmacological support for clinical trials in the CCR, including designing clinical pharmacokinetic and pharmacodynamic studies, the development of drug assays using a variety of state of the art methods and the measurement of drug concentrations in patient samples, and the analysis of pharmacokinetic and pharmacodynamic data generated by our Section or by pharmaceutical companies. The central nervous system (CNS) pharmacology of anticancer drugs is also studied because of the high incidence and dire consequences of primary and metastatic CNS cancers in children. The CNS pharmacology of anticancer drugs is studied in a non-human primate model with indwelling ventricular catheters that allow for sampling of the cerebrospinal fluid (CSF) and drug administration into the lateral ventricle. 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. Examples of agents recently studied include erlotinib, ABT-751, anakinra, PXD101, talabostat, and O4-benzylfolate, sorafenib, and satraplatin. Microdialysis is also used to measure extracellular fluid drug concentration in brain tissue and to relate brain drug concentration to the drug concentration in other tissues and the cerebrospinal fluid. In addition, strategies to pharmacologically modulate the BBB have been 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 a focus of research.
