This contract provides a resource for conducting the following types of studies with agents selected for preclinical development by the Developmental Therapeutics Program, NCI: (1) development of analytical methods to quantify compounds in plasma, urine, and other biological matrices at levels corresponding to the expected therapeutic and/or toxic range;(2) plasma stability and protein binding studies, which are conducted at an early stage of compound development to ensure proper sample handling and to aid in the interpretation of animal studies;(3) pharmacokinetic characterization following administration to animals by various routes and schedules, including a determination of oral bioavailability where appropriate;(4) quantification and identification of drug metabolites generated in vivo and in various in vitro systems (e.g., S9 fractions, microsomes, hepatocytes, P450 isoforms, liver slices);and (5) assessment of pharmacodynamic effects in tumor or surrogate tissues and correlation of these effects with drug levels and/or total drug exposures. It is anticipated that the data obtained from detailed pharmacokinetic investigations will be useful in the design of preclinical efficacy and toxicology studies and Phase I clinical trials of selected agents. Technical reports submitted by the contractors will be included in INDs submitted to the FDA by the NCI or other institutions. Compounds selected for study under this contract may arise from a variety of peer-reviewed extramural sources such as the Division of Canter Treatment Drug Development Group (DDG) for potential NCI-held Investigational New Drug (IND) applications and the Rapid Access to Intervention Development (RAID) and Rapid Access to NCI Discovery Resources (R*A*N*D) Programs for investigator-held INDs. In addition, development projects also arise from other pipelines such as the NCI Development of Clinical Imaging Agents and Enhancers (DCIDE) program, the NIDDK Type-1 Diabetes RAID program, and the NIH Roadmap RAID Program (which provides support for development of candidate agents in many therapeutic categories). The NCI intramural program has also been a source of anticancer compounds for study.
