Preclinical Studies of Antineoplastic Drug Metabolism and Disposition
The CPAF has been critical to the successful competition for and completion of a variety of UPCI program projects funded by the National Cancer Institute (NCI). Among the most prominent of these are contract N01-CM-52202, "Preclinical pharmacology studies of antineoplastic and antiretroviral agents," and its successor N01-CM-07014-39, "Preclinical Pharmacological Studies of Antitumor and Anti-HIV Agents," which is one of five such contracts funded by the NCI to develop information in support of molecules proposed for subsequent clinical trials.
The facility has developed and validated assays for zebularine, 2,2-dimethylbutyrate, benzaldehyde dimethane sulfonate and metabolites, gemcitabine and dFdU, tetrahydrouridine, 5-fluoro-2'-deoxycytidine and its metabolites, and the novel indenoisoquinoline topoisomerase inhibitors LMP400 and LMP776. These assays have primarily involved LC-MS or LC-MS/MS instrumentation, and have been applied to animal and human PK studies performed at UPCI or elsewhere as part of NCI-funded toxicology programs working with the same agents sent to the UPCI for animal pharmacokinetic studies. With the exception of zebularine, all of the agents for which the CPAF developed assays and performed preclinical studies under this contract are currently in NCI-sponsored clinical trials; the assay and pharmacokinetic data generated by the facility served as part of the IND submitted to the FDA, and the assays continue to support the clinical efforts.
The CPAF has also provided important support to program project grant 5P30CA047904-160002, "Molecular Therapeutics and Drug Discovery Program." The facility developed assays for JR-oxime, DA-3003-1, the Myc-Max disruptor 10074-G5, 23-TZD, kb-NB142-70, and kb-NB184-43, and then applied those assays to murine PK studies and for quantitation of parent compound in plasma and other biological matrices in preclinical models. The CPAF has identified numerous metabolites of many of the agents listed above.
In addition, CPAF provides analysis of vitamin D and its metabolism, assays for the photodynamic therapy agent Pc4, and assays for tetrahydrouridine and 5-fluoro-2'-deoxycytidine. These assays continue to be employed in a number of NCI-sponsored preclinical and clinical studies of the combination of those agents, including an NCI-sponsored program project evaluating triacetyl tetrahydrouridine as a prodrug for successful oral delivery of tetrahydrouridine.
Clinical Studies of Antineoplastic Drug Metabolism and Disposition
Outside of UPCI, the facility's quality and capacity has been recognized through its designation as the central reference analytical and pharmacokinetic modeling resource for phase IV clinical studies of imatinib, nilotinib, dasatinib, and ixabepilone, and its continued serving as the pharmacology core laboratory for the Gynecological Oncology Group (GOG, becoming NRG) and the Cancer and Leukemia Group B (CALGB, now Alliance).
In addition, the CPAF has served as the NCI reference laboratory to support phase I studies involving veliparib and vorinostat, and is currently serving as the reference laboratory for a belinostat hepatic dysfunction study (quantitating benlinostat and 5 metabolites), and a veliparib hepatic and renal dysfunction study (quantitation of veliparib and major metabolite M8).
The CPAF provides assays for ATRA, belinostat, benzaldehyde dimethanesulfonate, busulfan, carboplatin, celecoxib, cisplatin, dasatinib, docetaxel, 5-fluoro-2'-deoxycytidine, 5-fluorouracil, gemcitabine, hydroxyurea, imatinib, ixabepilone, LMP400, LMP776, letrozole, nilotinib, PEITC, paclitaxel, RO4929097, temozolomide, tetrahydrouridine, veliparib (ABT-888), and vorinostat.
The UPCI CPAF serves numerous other medical institutions and pharmaceutical companies. Academic partners include Memorial Sloan-Kettering Cancer Institute, University of Texas at San Antonio, Oregon University of Health Sciences, Medical College of Virginia, Case Western Reserve University, New York University, University of Wisconsin, Wayne State University, City of Hope, Washington University, Ohio State University, Texas Children's Hospital, University of Rochester, and the AIDS Malignancy Consortium. Industrial partners include Novartis, Eli Lilly, Bristol Myers-Squibb, and Aventis, among others.