Figure 5.

Single administration plasma pharmacokinetic profiles of trametinib (5.0 mg/Kg) and sapanisertib (2.0 mg/Kg), or combination, were associated with respective target inhibition in tumor xenografts. Plasma samples and tumor tissues were collected at 2, 4, 6, 8, 12, 24 and 48 hours after administration of inhibitors, two mice per treatment group per time point. The plasma pharmacokinetics of trametinib alone (black tracing) or in combination with sapanisertib (purple tracing) A), or of sapanisertib alone (red tracing) or with trametinib (purple tracing) B), were determined using mass spectrometry. Maximum concentration (C_max), time of ½ clearance (T_1/2), and the plasma concentration over time (AUC_LAST) are indicated for individual inhibitors when administered alone and in combination (single/combination). † (p<0.001). C) Target inhibition in tumor tissues by western blot. Selected representative tumor samples are shown to demonstrate the activity changes of ERK, AKT and S6 over the course of 48 hours post single oral treatment with trametinib (T), sapanisertib (S) and the combination (T+S).