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Additional blood samples for PK analysis were obtained on days 2 and 16 of cycl

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 Additional blood samples for PK analysis were obtained on days 2 and 16 of cycl Empty Additional blood samples for PK analysis were obtained on days 2 and 16 of cycl

Сообщение  wangqian в Вт Май 13, 2014 3:04 pm

Safety and tolerability of dinaciclib were assessed based on review of laboratory test results, electrocardiograms, vital signs, physical examinations, and reported adverse events, Any abnormal laboratory results that led to hospitalization, resulted in a change in dosing, or were medically ABT-888 significant were reported as AEs. Adverse events were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events and were coded using the Medical Dic tionary for Regulatory Activities, Pharmacodynamic and pharmacokinetic assessments The antiproliferative activity of dinaciclib was assessed ex vivo using whole blood samples obtained on days 1 and 15 of cycle 1, predose on day 8 of cycle 1, and on day 22 of cycle 1.<br><br> Whole blood isolated from subjects was treated with phytohemagglutinin to stimulate cell division in lymphocytes. Following a brief 30 minute exposure to AEB071 分子量 bromodeoxyuridine, cells were harvested and stained using an FITC conjugated antibody specific for BrdU, counterstained with propidium iodide RNase A, and analyzed using a FACSCalibur flow cytometer. Approximately 35% to 40% of the CD45 positive cells in the whole blood incorporate BrdU follow ing PHA stimulation under conditions defined in this assay, signifying DNA synthesis and cell division. Any subject with less than 5% BrdU incorporation post treat ment was classified as a responder to dinaciclib treatment. To explore the relationship between exposure and bio activity of dinaciclib,%BrdU incorporation was correlated with the amount of dinaciclib found in plasma samples taken at the same time.<br><br> Skin punch biopsies were obtained before and 4 hours after treatment with dinaciclib, and fixed in 10% buffered AG-014699 価格 formalin for immunohistochemistry ana lysis. The phosphorylation status of the Rb protein in the proliferative layer of skin and in the proliferating cells at the base of hair follicles was determined by IHC utilizing a rabbit anti phospho Rb antibody diluted to 0. 83 ug mL or 0. 67 ug mL. Immunohistochemistry staining was scored 0, 1, 2, or 3 , H score was calculated as a measure of overall immunoreactivity in a given sample, using the following formula, H score × 3 × 2 × 1. Subjects were to be categorized as re sponders if no degree of staining was detected with the anti phospho Rb antibody.<br><br> Pharmacodynamic effects were further assessed by moni toring decreased metabolic activity following IV infusion of dinaciclib using FDG PET CT scans, conducted within 14 days prior to the first dose of dinaciclib and on day 22 of cycle 1, unless treatment was delayed. Metabolic activity data were obtained for research use only and were not used for clinical management of subjects. A 30% reduction in posttreatment standardized uptake value, in up to 6 lesions prospectively identified at the start of treatment as the most representative meta bolically active sites of disease, was used to determine responders and nonresponders to dinaciclib treatment. Dinaciclib plasma concentrations were analyzed on days 1 and 15 of cycle 1 prior to the start of infusion, and at 1 hour, 2 hours, 2 hours 15 minutes, 2 hours 30 minutes, 3 hours, 3 hours 30 minutes, 4 hours, 5 hours, 6 hours, and 8 hours after the start of the infusion.


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