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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 PK describes rat neutrophil counts.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 Cmax for each schedule tested. D) R2 plotted for Cavg,ndays for n-days from 1 to 14 days. E) The corresponding p-values of the Cavg,ndays correlation showing correlation. F) Normalized ANC nadir is highly correlated with max(Cavg,4days) with R2 = 0.70 (p<0.05), a better correlation than either Cmax or AUC.
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pone-0109892-g005: Moving average PK describes rat neutrophil counts.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 Cmax for each schedule tested. D) R2 plotted for Cavg,ndays for n-days from 1 to 14 days. E) The corresponding p-values of the Cavg,ndays correlation showing correlation. F) Normalized ANC nadir is highly correlated with max(Cavg,4days) with R2 = 0.70 (p<0.05), a better correlation than either Cmax or AUC.

Mentions: We next sought to determine if the PK parameter determined from the model was appropriate for analyzing in vivo data. To this end, we measured ANC levels in rats after administration of TAK-960, an investigational inhibitor of Polo-Like Kinase (PLK), a target known to induce neutropenia [43]. A variety of schedules and dose levels were tested to study the correlation between ANC nadir and PK in this system, each giving a different Cmax and AUC which were calculated from a rat PK model (Figure S4). The time-course of circulating neutrophils was then assessed and normalized to control (Figure 5a). From this, the PK-ANC correlation was tested for AUC (Figure 5b) and Cmax (Figure 5c), and shows a weak correlation for both (R2 = 0.18 (p = 0.40) and R2 = 0.09 (p = 0.55)), respectively. Since rat neutrophil development has a different timescale than in human [36] we again adjusted the n-days over which we tested the maximal moving average correlation with neutrophil nadir. For n-day values between 3 and 6, the correlation is strong (R2 = 0.70) and statistically significant (p<0.05) (Figure 5d-5e). The ∼3- fold difference between the nadir-predictive moving average between human (16 days) and rat (3–6 days) can be explained by the differences in the mean transit time in the human and rat neutropenia models [26], [36].


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 PK describes rat neutrophil counts.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 Cmax for each schedule tested. D) R2 plotted for Cavg,ndays for n-days from 1 to 14 days. E) The corresponding p-values of the Cavg,ndays correlation showing correlation. F) Normalized ANC nadir is highly correlated with max(Cavg,4days) with R2 = 0.70 (p<0.05), a better correlation than either Cmax or AUC.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0109892-g005: Moving average PK describes rat neutrophil counts.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 Cmax for each schedule tested. D) R2 plotted for Cavg,ndays for n-days from 1 to 14 days. E) The corresponding p-values of the Cavg,ndays correlation showing correlation. F) Normalized ANC nadir is highly correlated with max(Cavg,4days) with R2 = 0.70 (p<0.05), a better correlation than either Cmax or AUC.
Mentions: We next sought to determine if the PK parameter determined from the model was appropriate for analyzing in vivo data. To this end, we measured ANC levels in rats after administration of TAK-960, an investigational inhibitor of Polo-Like Kinase (PLK), a target known to induce neutropenia [43]. A variety of schedules and dose levels were tested to study the correlation between ANC nadir and PK in this system, each giving a different Cmax and AUC which were calculated from a rat PK model (Figure S4). The time-course of circulating neutrophils was then assessed and normalized to control (Figure 5a). From this, the PK-ANC correlation was tested for AUC (Figure 5b) and Cmax (Figure 5c), and shows a weak correlation for both (R2 = 0.18 (p = 0.40) and R2 = 0.09 (p = 0.55)), respectively. Since rat neutrophil development has a different timescale than in human [36] we again adjusted the n-days over which we tested the maximal moving average correlation with neutrophil nadir. For n-day values between 3 and 6, the correlation is strong (R2 = 0.70) and statistically significant (p<0.05) (Figure 5d-5e). The ∼3- fold difference between the nadir-predictive moving average between human (16 days) and rat (3–6 days) can be explained by the differences in the mean transit time in the human and rat neutropenia models [26], [36].

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