During FY13, the Clinical Pharmacology Program (CPP) provided support to over 80 clinical trials. This support ranged from sample pickup and processing, to full analytical method development and validation, pharmacokinetic and pharmacogenetic analysis and assistance with trial design. In FY13, the CPP processed over 30,000 biological samples including blood, urine and ascites. Upon arrival, all samples are processed, barcoded and frozen for future use. The first priority in characterizing the pharmacokinetics of an anticancer agent is to develop a reliable and reproducible analytical method for quantitating agents in biological fluids and tissues. The CPP utilizes high performance liquid chromatography (HPLC) coupled with state-of-the-art detection instruments including mass spectrometers, tandem mass spectrometers (MS/MS) and diode array detectors (for UV absorption) to measure drug concentrations. Following method development, assays are validated according to the FDA Guidelines for Bioanalytical Method Development. The CPP is currently focused on the method development, validation and subsequent human sample analyses for imatinib, belinostat, clopidogrel, bortezomib, and irinotecan. The CPP has previously developed analytical methods for a wide range of other therapeutics, including depsipeptide, TNP-470, phenylacetate, phenylbutyrate, tamoxifen, UCN-01, CAI, thalidomide, COL-3, suramin, melphalan, erlotinib, perifosine, SU5416, 2ME, MS-275, ketoconazole, lenalidomide, romidepsin, AZD2281 and gemicitabine, sorafenib, finasteride, nelfinavir, and 17-DMAG. To evaluate the pharmacokinetics (PK) of AZD2281 and gemcitabine as well as to assess for any potential drug-drug interaction, a sensitive and simple LC-MS method was recently developed to simultaneously determine drug concentrations of both AZD2281 and gemcitabine on patient samples derived from this trial. We have recently validated and published a simple, rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) analytical method for quantification of Hsp90 inhibitor PF-04928473 in human plasma, following administration of its prodrug, PF-04929113 (SNX5422). We have developed a sensitive and rapid Ultra-HPLC-MS/MS method for the simultaneous detection of clopidogrel and its MPB-derivatized active thiol-metabolite (CAMD) in human plasma. Derivatization of the active metabolite in blood with 2-bromo-3'-methoxy acetophenone (MPB) immediately after collection ensured metabolite stability during sample handling and storage. The analytical method measured concentrations of clopidogrel and CAMD with accuracy (%DEV) and precision (%CV). The method was successfully applied to measure the plasma concentrations of clopidogrel and CAMD in three subjects administered single oral doses of 75, 150, and 300 mg clopidogrel. It was further demonstrated that the derivatizing agent (MPB) does not affect clopidogrel levels, thus from one aliquot of blood drawn clinically, this method can simultaneously quantify both clopidogrel and CAMD with sensitivity in the picogram per mL range. Irinotecan drug eluting beads study: An analytical method was developed and validated for the quantitative determination of irinotecan, its active metabolite SN38, and glucuronidated SN38 (SN38-G) in both porcine and human plasma by ultra high-performance liquid chromatography-tandem mass spectrometry and its application to hepatic chemoembolization. The method was validated in both human and porcine plasma with comparable accuracies and precisions within the generally acceptable range. The validated method was applied to both preclinical and clinical trials involving hepatic chemoembolization of irinotecan drug-eluting beads to study the pharmacokinetics of the three analytes. Preformulation Study of NSC-726796: A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its threemain degradation products was developed. This method was used to investigate its degradation kinetics and mechanism.
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