PHARMACOKINETICS/PHARMACODYNAMICS OF ANTICANCER DRUGS IN CHILDHOOD SOLID TUMORS

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Treatment failure in children with malignant solid tumors may be directly related to variability in anticancer drug disposition. However, children with cancer usually receive identical drug dosages, based on body size, without accounting for pharmacokinetic variability. Clinical pharmacokinetic-pharmacodynamic investigations in children are ofter descriptive, while animal models provide greater flexibility in designing preclinical hypothesis-testing studies. This project focuses on the application of pharmacokinetic/dynamic methodologies to characterize concentration-effect relationships of anticancer drugs in animal model systems, and to develop rational drug therapy regimens for the treatment of children with solid tumors, with particular emphasis on camptothecin analogs. The specific aims of this project are: 1) to establish parmacokinetic-pharmacodynamic relationships of camptothecin anticancer drugs in human tumor xenograft models; 2) to determine the concentration profile of camptothecins in the extracellular fluid (ECF) of xenografts; 3) to elucidate the underlying mechanisms responsible for altered drug disposition in tumor-bearing mice compared to nontumor-bearing mice; 4) to develop a pharmacokinetic model to predict disposition of camptothecins in the CSF; and 5) to identify the optimal schedules and pharmacokinetic exposures producing antitumor activity for other new agents. These aims will be addressed primarily with the murine pediatric tumor xenograft model and in nonhuman primates to characterize cerebrospinal fluid disposition of drugs. Models of drug distribution into extracellular fluid (ECF) will be developed and validated using microdialysis methods. Within this program, the concentrations, exposure times, and intervals between exposures that optimize cytotoxicity will be characterized in vitro. In this project, these studies will be extended in vivo, using unique xenograft models of childhood solid tumors, to evaluate systemic exposure, tissue exposure, and tumor responses, and to construct pharmacodynamic models for clinical use. Studies of ECF and plasma drug concentrations will determine whether rates or duration of drug administration alter distribution into tumor tissues. Laboratory studies will be undertaken to identify altered drug metabolism pathways in mice bearing xenographs, compared to normal mice. Translation of the findings from this project will be incorporated into clinical studies to develop optimal dosing regimens and to verify the relatonships identified in the animal models.