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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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Moving average of PK describes neutropenia.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(Cavg,16day), accounts for most of the variability in median ANC nadir across total dose and schedule (R2 = 0.86, p<0.01).
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pone-0109892-g003: Moving average of PK describes neutropenia.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(Cavg,16day), accounts for most of the variability in median ANC nadir across total dose and schedule (R2 = 0.86, p<0.01).

Mentions: Based on the prediction that frequent low doses of docetaxel would induce less neutropenia than infrequent large doses, we hypothesized the existence of a PK parameter for each schedule that would correlate directly with the simulated ANC nadir. To this end, we first examined two common PK parameters, Cmax and total cycle AUC, for correlation with the median ANC nadir. The schedule-dependent Cmax correlates poorly with the median ANC nadir (R2 = 0.10, p<0.05; Figure 3a). The total cycle AUC was also tested to see if it could explain the schedule-to-schedule differences in ANC nadir. The very low correlation between total cycle AUC and the median ANC nadir (R2 = <0.01, p>0.75) suggests that AUC alone is not fully accounting for the neutropenia effect. It is not surprising that AUC is not correlated, since total cycle AUC should be constant for linear PK and a fixed 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)

Moving average of PK describes neutropenia.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(Cavg,16day), accounts for most of the variability in median ANC nadir across total dose and schedule (R2 = 0.86, p<0.01).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4215876&req=5

pone-0109892-g003: Moving average of PK describes neutropenia.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(Cavg,16day), accounts for most of the variability in median ANC nadir across total dose and schedule (R2 = 0.86, p<0.01).
Mentions: Based on the prediction that frequent low doses of docetaxel would induce less neutropenia than infrequent large doses, we hypothesized the existence of a PK parameter for each schedule that would correlate directly with the simulated ANC nadir. To this end, we first examined two common PK parameters, Cmax and total cycle AUC, for correlation with the median ANC nadir. The schedule-dependent Cmax correlates poorly with the median ANC nadir (R2 = 0.10, p<0.05; Figure 3a). The total cycle AUC was also tested to see if it could explain the schedule-to-schedule differences in ANC nadir. The very low correlation between total cycle AUC and the median ANC nadir (R2 = <0.01, p>0.75) suggests that AUC alone is not fully accounting for the neutropenia effect. It is not surprising that AUC is not correlated, since total cycle AUC should be constant for linear PK and a fixed 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