According to the calculation, the δA/δT value for all three dosing schemes was approximately 2mg/hr. The higher exposures observed from the longer

dosing interval were attributed to the increased absorption time (Figure 5). Figure 3 Compound 1 50mg/Kg X3 tandem dose (2.5hr interval) Idelalisib CLL Predicted versus observed exposure. Figure 4 Compound 1 50mg/Kg X3 tandem dose (1, 1.5, and 2.5hrs interval) exposure comparison. Figure 5 The 50mg/kg X3 Tandem Dose Wagner-Nelson Plot (Cabozantinib cost presented as mean values). For the 100mg/Kg tandem dosing groups, similar impacts were observed when the dose interval changed. In general, the Inhibitors,research,lifescience,medical shortest dosing interval (1hr) gave the lowest exposures. Again, it is hypothesized with such a short interval, drug “overlapped” from dose to dose which caused the nonabsorbable portion to increase thereby reducing the exposure Inhibitors,research,lifescience,medical (similar to an s.i.d. dose). Better drug delivery efficiency was achieved when the dose interval increased to 1.5 and 2.5hrs. The Cmax and AUC (Tables ​(Tables44 and ​and5)5) obtained from both dosing schemes Inhibitors,research,lifescience,medical are comparable and well exceed the values from the s.i.d. dose (Table 2 300mg/kg). This suggests that for this dose (100mg/Kg X3) 1.5hrs may be sufficient to separate two doses as well. However, it is worth noticing that the variability

of data obtained from the 1.5hr interval is higher than that of the 2.5hr interval. This suggests that the 1.5hr interval

may not be ideal for higher doses as the risk of drug overlap in the GI is higher and may have contributed to the higher variability in exposures. The simulated exposure (2.5hrs interval) versus the obtained exposure for Inhibitors,research,lifescience,medical the 100mg/kg X3 tandem dose is presented in Figure Inhibitors,research,lifescience,medical 6, and the AUC/Dose (for 2.5hr interval) was calculated to be 1.03±0.05μM*hr/mg/kg. Based on the linear model and exposures obtained from the 1.5 and 2.5hr intervals, a noticeably increased beta phase half-life was observed from the tandem doses versus the predicted curve. It is possible that via accumulation the drug exposure has reached the nonlinear range (saturated the CL), and therefore a linear PK model underpredicts the beta phase half-life. Carfilzomib A Wagner-Nelson plot (see Section 2) was used to calculate drug absorbed and to assess the absorption as a function of time and is presented as Figure 7. Again, the higher exposures observed from the longer dosing interval were attributed to increased absorption time. Figure 6 The 100mg/kg X3 Tandem Dose Predicted (2.5hr) versus Obtained Exposures from 1, 1.5, and 2.5hrs interval. Figure 7 The 100mg/kg X3 Tandem Dose Wagner-Nelson Plot (presented as mean values). Table 4 Tandem dose scheme AUC comparison (μM*hr). Table 5 Tandem dose scheme average Cmax comparison (μM). For the 200mg/Kg tandem dosing groups, a much bigger impact was observed when dose interval changed.