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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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Model structure and simulated ANC time-course.(A) The structure of semi-mechanistic pharmacokinetic-pharmacodynamic Friberg model (from ref [26]) 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.
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pone-0109892-g001: Model structure and simulated ANC time-course.(A) The structure of semi-mechanistic pharmacokinetic-pharmacodynamic Friberg model (from ref [26]) 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.

Mentions: Clinical observations have shown that even for constant total dose per cycle, different dose schedules (e.g. frequency of dosing or infusion time) can lead to very distinct neutrophil dynamics and incidence of neutropenia [22], [27], [34], [36], [39]–[42]. Therefore, we used the Friberg model of neutropenia to study in detail how drug plasma time course correlated with incidence or severity by employing previously published semi-mechanistic population PK-PD models (Figure 1a) built from clinical ANC profiles following treatment with docetaxel [26], [34].


Dose schedule optimization and the pharmacokinetic driver of neutropenia.

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

Model structure and simulated ANC time-course.(A) The structure of semi-mechanistic pharmacokinetic-pharmacodynamic Friberg model (from ref [26]) 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.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0109892-g001: Model structure and simulated ANC time-course.(A) The structure of semi-mechanistic pharmacokinetic-pharmacodynamic Friberg model (from ref [26]) 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.
Mentions: Clinical observations have shown that even for constant total dose per cycle, different dose schedules (e.g. frequency of dosing or infusion time) can lead to very distinct neutrophil dynamics and incidence of neutropenia [22], [27], [34], [36], [39]–[42]. Therefore, we used the Friberg model of neutropenia to study in detail how drug plasma time course correlated with incidence or severity by employing previously published semi-mechanistic population PK-PD models (Figure 1a) built from clinical ANC profiles following treatment with docetaxel [26], [34].

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