The role of pharmacokinetics (PK) and pharmacodynamics (PD) has increased dramatically as anticancer drug discovery and development has shifted towards molecularly-targeted therapies. Increased appreciation of PK/PD relationships has resulted in greater emphasis on generating and analyzing such data, even for agents without defined molecular targets. Recognition of drug-drug interactions and pharmacogenetic differences in drug metabolism, disposition, and susceptibility has increased the need for assays to define relevant polymorphisms and their clinical impact. The Clinical Pharmacology Analytical Facility (CPAF) was established in 1994 to provide state-of-the-art pharmacology research facilities forthe University of Pittsburgh Cancer Institute (UPCI). The CPAF occupies 1,000 square feet of laboratory space in the Research Pavilion of the Hillman Cancer Center. The CPAF supports many UPCI CCSG programs in addition to the extensive UPCI preclinical and clinical pharmacology research activities ofthe Molecular Therapeutics and Drug Discovery Program. Services include quantitation of drugs, metabolites, and other materials;identification of metabolites;and PK and PD analyses of anticancer agents undergoing preclinical and/or clinical evaluation at UPCI. The CPAF also uses in vitro methods such as human hepatocyte cultures and subcellular fractions, such as microsomes and cytosol, to characterize the cytochrome P450 isoforms and other key drug-metabolizing enzymes responsible for producing metabolites identified. The CPAF provides important consultative services to UPCI investigators on the design of pharmacologic studies and drug assays, metabolism, and PK analyses. The CPAF is co-directed by Drs. Merrill J. Egorin and Jan H. Beumer and overseen by an advisory committee representing the Schools of Medicine and Pharmacy, and the Biostatistics Facility. During the past 6 years, the CPAF has provided support for 21 Cancer Therapy Evaluation Program (CTEP)-sponsored clinical trials at UPCI, 10 investigator-initiated clinical trials at UPCI, 28 CTEP-sponsored clinical trials at other NCI-designated cancer centers or cooperative groups, and 35 animal pharmacology projects. It also provided analytical chemistry support for 3 in vitro pharmacology studies. To expand its capabilities and increase its value, the CPAF has enhanced substantially its analytical chemistry instrumentation, its PK modeling software, and its personnel. Since the last competitive renewal of the UPCI Cancer Center Support Grant, the Facility has acquired an additional 2 LC-MS instruments and 2 LC-MS/MS instruments. Also since the last competitive renewal, the CPAF competed successfully to serve as the Pharmacology Core Laboratory for the Gynecologic Oncology Group and successfully recompeted its role as the Pharmacology Core for the Cancer and Leukemia Group B. The CPAF continues to be a major collaborator of the University of Southern California Biomedical Simulations Resource, thereby allowing the CPAF to implement sophisticated PK and PD modeling software. The requested CCSG funding will support Facility personnel for their efforts in providing consultative services related to assay development, methodology, protocol design, and data interpretation, and their efforts to ensure that instrumentation and software are suitably maintained and available for application to projects by investigators seeking support from the Facility.
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