Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia
Figure 2
Effect of schedule on docetaxel induced neutropenia.
Summary of population simulation of PK-ANC model for 1000 virtual individuals at two total dose levels of docetaxel shows constant dosing induces a less severe nadir than punctuated dosing. Population median ANC nadir for low (A) total dose and high (C) total dose as well as probability of grade 4 neutropenia (nadir <0.5×109/L) are shown for low (B) and high (D) dosing total dose levels. Each plotted captures schedules with the “days-on/days-off” format with number of consecutive days on in given treatment period shown on the X-axis and treatment period (sum of days on and days off) on the Y axis. Population estimation of median ANC nadir and probability of grade-4 neutropenia compared with common PK parameters across variety of schedules for low (blue) and high (red) total dose. (E) Cmax plotted against median ANC nadir for each of the schedules tested and shows weak correlation of −0.32 (R2 = 0.10, p<0.01). (F) Total cycle AUC over all schedules shows overall correlation of −0.64 (R2 = 0.41, p<0.01) with median ANC nadir, but the correlation is mainly driven by the differences in total dose as it loses ability to predict neutropenia at a fixed total dose level (R2<0.01 and p>0.75 at low and high total dose).