We currently have several active protocols approved by the Animal Care and Use Committee for preclinical pharmacokinetic analysis of new agents,a continued collaborative relationship with the Pharmacology and Experimental Therapeutics Section of the POB, and a new collaborative relationship with the Molecular Pharmacology Section (Doug Figg) of NCI to partner in pharmacologic investigations of new agents. We have successfully obtained new agents from intramural and extramural sources to evaluate, and are developing biomarkers in the preclinical setting. In general, for an antitumor agent to have an effect, you need: a) an active agent, b) Delivery to tumor c) it must be present at tumor site in its active form, d) Effective concentrations, e) Long enough period of time (i.e.e effective exposure) and f) Tolerability at doses necessary to achieve above. For targeted therapy, we need to know if the target is present. We are developing methods to further investigate the mechanisms of action of agents currently in clinical trials, and investigate biomarkers or surrogate markers of drug activity and tumor response. We have developed a new animal model for brain microdialysis in an effort to determine if cerebrospinal fluid penetration is an appropriate surrogate for CNS tissue penetration. We are also evaluating effects of common concurrent medications such as steroids on the pharmacokinetics of chemotherapeutic agents.
