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Results: 3

1.
Figure 1

Figure 1. Sorafenib N-oxide is a potent FLT3 inhibitor. From: A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias.

A. Standard curve generated as described previously(17), from western blot of TF-ITD cells in plasma exposed for one hour to increasing concentrations of sorafenib. B. Standard curve generated with sorafenib N-oxide in plasma.

Keith W. Pratz, et al. Leukemia. ;24(8):1437-1444.
2.
Figure 2

Figure 2. PIA results for patients receiving sorafenib. From: A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias.

Plasma was isolated from whole blood samples obtained from patients receiving increasing doses of sorafenib on the clinical trial. Samples were obtained immediately prior to dosing on Days 1, 8, and 15 and 29 of each cycle. Dose levels 1, 2, and 3 correspond to total daily doses of 800, 800, and 1200 mg, respectively (see Table 1). Shown are the results from representative patients on successively higher dose levels using the PIA assay on TF-ITD cells for phosphorylated FLT3 (left) and ERK (right). For dose level 2 and 3, extra time points on Day 1 show complete silencing of FLT3 activity within 2 hours of the first dose with maintenance of this inhibition throughout the treatment cycle. Vertical lines have been inserted to indicate a repositioned gel lane.

Keith W. Pratz, et al. Leukemia. ;24(8):1437-1444.
3.

Figure 3. PIA results compared with standard curve for Sorafenib. From: A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias.

A. Plasma was collected from patients receiving sorafenib prior to dosing on day 1, 8, 15, and 29. The plasma samples underwent conventional pharmacokinetic analysis of concentrations of sorafenib and sorafenib N-oxide. In parallel, plasma from the same time points were examined in PIA assays for assessment of FLT3 and ERK inhibition potential. On the × axis the results of the pharmacokinetics are plotted for sorafenib. On the y axis, the degree of FLT3 inhibition, as assessed by PIA, is plotted as a percent of control. This data is overlaid by the standard curve for sorafenib in plasma as generated in TF-ITD cells(solid line, see Figure 1A). B. PIA results, as described in panel A, of P-ERK compared to standard curve for sorafenib inhibition of P-ERK(solid line). C. The PIA assay values for FLT3 inhibition were replotted after adjusting the “effective” sorafenib concentrations by adding the amount sorafenib N-oxide multiplied by its potency factor using the equation: Adjusted sorafenib concentration=Sorafenib + (Sorafenib N-Oxide*14.59). D. The same experimental data generated from analysis of P-Erk and corrected for sorafenib N-oxide as described in panel C.

Keith W. Pratz, et al. Leukemia. ;24(8):1437-1444.

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