or three times daily to eligible patients on day 1 only of their second, or subsequent, cycle and then administered, again at the same dose as administered intravenously, in a further cohort of patients once daily on days 15 of the second or third cycle. All other doses in all subsequent cycles were administered intravenously. Toxicities were assessed Imatinib weekly and graded and reported according to NCI CTCAE v3.0. Patient assessments for toxicity and anti tumour activity were not inXuenced by participation in this sub study of oral administration of belinostat. Dose limiting toxicity was based on the toxicities observed in the Wrst 21 day cycle of intravenous belinostat. However, patients participating in the oral dosing sub study were observed for any toxicity in addition to those seen with intravenous treatment.
Drug preparation and administration Belinostat was supplied by Topotarget, Copenhagen, Denmark. Belinostat powder was formulated in standard gelatine capsules containing 250 mg for oral administration. Patients were not required to fast prior to drug administration.Lithium heparinised blood samples were placed on ice then centrifuged at 4°C. Two millilitre aliquots of Imiquimod molecular weight plasma were stored at 70°C until analysis. The concentration of belinostat in plasma was analysed by liquid chromatography with tandem mass spectrometry detection as previously described . PK calculations were performed using a non compartmental method . The area under the plasma concentration time curve was calculated using the linear trapezoid method and uniform weighting, and the elimination half life was calculated by the log linear method.
Pharmacodynamic azelastine price studies Histone hyperacetylation in peripheral blood mononuclear cells Histone acetylation was evaluated by Western blotting for histone H4 on histones isolated from peripheral blood mononuclear cells . Samples for histone acetylation were taken at various time points after intravenous administration of belinostat in cycle 1 and after oral administration in cycle 2. Blood samples Lopinavir ic50 were collected in lithium heparin vacutainer tubes, placed on ice and processed immediately using a modiWcation of the method described by Yoshida et al. and as previously described . Densitometry was carried out on the resulting Western blots and the results were expressed relative to a control sample . The same cell line standard was used in all blots.
AUC for histone acetylation was calculated phosphorolysis by non compartmental analysis using WinNonLin Version 4.0 software . Results Patient characteristics A total of 46 patients were recruited into the phase 1 trial of belinostat, by intravenous administration, between October 2003 and February 2006 as previously reported . Fifteen of these patients were also enrolled into this sub study of oral belinostat between August 2004 and January 2006. Details of the oral dosing schedule for each patient are summarised in Table 1. One patient received two schedules of oral belinostat in diVerent treatment cycles. Baseline characteristics for these 15 patients are summarised in Table 2. Toxicity assessments There were no toxicities, in addition to those observed with the intravenous formulation, in any of the 15 patients who were treated in this sub study with oral belinostat.