Model structure and simulated ANC time-course.

<p>(A) The structure of semi-mechanistic pharmacokinetic-pharmacodynamic Friberg model (from ref <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109892#pone.0109892-Friberg1" target="_blank">[26]</a>) used to describe cytotoxic effect of drugs on proliferating neutrophils. Drug PK was linked to the semi-mechanistic PD model for neutrophil kinetics and unique PK-ANC profile for given drug at various schedules was generated. (B) Docetaxel PK-ANC simulation was carried out at an equivalent total dose to 100 mg/m² every 21 days. The plots show the plasma PK profile (blue lines) and ANC upon treatment (red lines) for schedules of 28 on-0 off, 7 on-21 off, 4 on-18 off, 1 on-9 off, 4 on–24 off and 1 on-27off.</p

Moving average of PK describes neutropenia.

<p>The maximum of the moving average concentration over the dosing interval was examined for its ability to predict the simulated median ANC nadir. (A) Example of the 16-day moving average calculated from concentration profile from 1on-9off dosing schedule. (B) The correlation between maximal moving average concentration and ANC nadir was calculated for sliding windows of 1 day to 28 days for low dose (blue squares), high dose (red circles), and combination (black line). The maximum ability to predict neutropenia for the combined low and high total doses occurs when the moving average is calculated over 16 days. (C) The maximum of the moving average concentration, max(C_avg,16day), accounts for most of the variability in median ANC nadir across total dose and schedule (R² = 0.86, <i>p</i><0.01).</p

Dose Schedule Optimization and the Pharmacokinetic Driver of Neutropenia

<div><p>Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an <i>in vivo</i> experimental system. Specifically, we find total AUC and C_max are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia <i>in vivo</i> following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection.</p></div

Moving average PK describes rat neutrophil counts.

<p>Rat neutrophil counts were measured response to the investigational PLK inhibitor TAK-960 and the relationship between plasma PK and neutrophil nadir was assessed. A) Absolute Neutrophil Count (ANC) normalized to control group plotted over the course of 21 days on a variety of dosing regimens. B) Normalized ANC nadir plotted versus total cycle AUC for each schedule tested. C) Normalized ANC nadir plotted versus the C_max for each schedule tested. D) R² plotted for C_avg,ndays for n-days from 1 to 14 days. E) The corresponding p-values of the C_avg,ndays correlation showing correlation. F) Normalized ANC nadir is highly correlated with max(C_avg,4days) with R² = 0.70 (<i>p</i><0.05), a better correlation than either C_max or AUC.</p

Equivalent total dose used in generation of simulated dosing schedules.

<p>Equivalent total dose used in generation of simulated dosing schedules.</p

Effect of schedule on docetaxel induced neutropenia.

<p>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) C_max plotted against median ANC nadir for each of the schedules tested and shows weak correlation of −0.32 (R² = 0.10, <i>p</i><0.01). (F) Total cycle AUC over all schedules shows overall correlation of −0.64 (R² = 0.41, <i>p</i><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 <i>p</i>>0.75 at low and high total dose).</p