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Dose schedule optimization and the pharmacokinetic driver of neutropenia.

Patel M, Palani S, Chakravarty A, Yang J, Shyu WC, Mettetal JT - PLoS ONE (2014)

Bottom Line: Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity.Further, we confirm this PK parameter for its ability to predict neutropenia in vivo 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.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.

ABSTRACT
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 in vivo experimental system. Specifically, we find total AUC and Cmax 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 in vivo 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.

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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).
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pone-0109892-g002: 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).

Mentions: ANC profiles were then simulated for a virtual population of 1000 patients for these schedules. Two different total dose levels, representing a high and low clinical dose range, were tested (Table 1). The results are shown in Figure 2a and 2c as a heat map of median ANC nadir (minimal absolute neutrophil count) for the simulated patient population under docetaxel treatment on a variety of schedules. Points along the diagonal in the plot (y = x) represent schedules with constant (QD) dosing. As can be seen in Figures 2a and 2c, the points in the upper left corner (e.g. a larger and less frequent dose) have a more severe ANC nadir compared to frequent dosing, and this trend is conserved both for low (Figure 2a) and high (Figure 2c) total dose.


Dose schedule optimization and the pharmacokinetic driver of neutropenia.

Patel M, Palani S, Chakravarty A, Yang J, Shyu WC, Mettetal JT - PLoS ONE (2014)

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).
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pone-0109892-g002: 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).
Mentions: ANC profiles were then simulated for a virtual population of 1000 patients for these schedules. Two different total dose levels, representing a high and low clinical dose range, were tested (Table 1). The results are shown in Figure 2a and 2c as a heat map of median ANC nadir (minimal absolute neutrophil count) for the simulated patient population under docetaxel treatment on a variety of schedules. Points along the diagonal in the plot (y = x) represent schedules with constant (QD) dosing. As can be seen in Figures 2a and 2c, the points in the upper left corner (e.g. a larger and less frequent dose) have a more severe ANC nadir compared to frequent dosing, and this trend is conserved both for low (Figure 2a) and high (Figure 2c) total dose.

Bottom Line: Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity.Further, we confirm this PK parameter for its ability to predict neutropenia in vivo 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.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.

ABSTRACT
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 in vivo experimental system. Specifically, we find total AUC and Cmax 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 in vivo 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.

Show MeSH
Related in: MedlinePlus