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

Additional blood samples for PK analysis were obtained on days 2 and 16 of cycle 1, on day 8 of cycle 1, and on day 1 of cycle 2, prior to and 2 hours after ABT-737 ic50 the start of the infusion. Plasma concentrations of dinaciclib were determined, as previously described, using validated high performance liquid chromatographic tandem mass spectrometry methods, Briefly, plasma samples were fortified with an internal standard dinaciclib in 1,1 ratio, loaded into a Water Oasis MCX Solid Phase Extraction plate, washed with phosphoric acid methanol, and eluted with methanol ammonium hydroxide. The eluent was evaporated and the extract injected into a LC MS MS. The retention time for dinaciclib and the internal standard was 2. 5 minutes and detection was performed using a Sciex API 5000 triple quadrupole LC MS MS system with a turbo ion spray source.<br><br> Key pharmacokinetic AEB071 溶解度 parameters evaluated for dinaciclib in cluded maximum observed plasma concentration, time of maximum plasma concentration, area under the plasma concentration time curve from time zero to infinity terminal phase half life, clearance, volume of distribution, and accu mulation ratio, Tumor response assessment Antitumor activity of dinaciclib on solid tumors was evaluated using CT or magnetic resonance imaging scans and Response Evaluation Criteria In Solid Tumors guidelines, Computed tomography or MRI scans were obtained within 4 weeks prior to the start of treatment with dinaciclib, and were repeated after every 2 cycles and at the poststudy assessment performed 4 weeks after the start of the last cycle.<br><br> Statistical analyses Demographic and baseline variables for each subject were tabulated and sum marized using descriptive statistics. No inferential ana lysis of safety data was planned, subjects reporting any AEs, the occurrence of specific AEs, and discontinuation due to AEs were summarized using descriptive statistics. AG-014699 分子量 For%BrdU incorporation, the re sponse rate and its 95% 2 sided exact confidence inter val were calculated if 6 or more responders were observed among 10 subjects, a level at which the lower limit of the 2 sided 95% exact CI was expected to be greater than 25%, allowing inference with high confi dence that the metabolic inhibition rate was more than 25%.<br><br> For each dose level, treatment effect on inhibition of lymphocyte proliferation was evaluated by comparing the pretreatment with the posttreatment%BrdU incorp oration on days 1 and 15 at specified posttreatment time points using a paired t test, For secondary endpoints, subjects were classi fied as responders or nonresponders and the response rate and its 95% CI were determined. Summary statistics were calculated using noncompartmental methods with the WinNonlin software for the concentration versus time data at each sampling time and for derived PK parameters. Results and discussion Subject disposition and baseline characteristics The study enrolled 52 subjects with histologically proven solid tumors for whom there was no known standard therapy or who had disease refractory to standard therapy. Treatment was administered to 48 subjects, 3 subjects were enrolled but did not meet protocol eligibility criteria and were never treated, and one subject who was enrolled did not receive any treatment because of an AE.