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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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Consistency of moving average of PK in describing severity of neutropenia across drugs.The maximum of the moving average concentration over the dosing interval was examined for its consistency to predict neutropenia across different drugs. Topotecan induced neutropenia was simulated using linear drug effect model while in case of Etoposide, simulation was carried out using nonlinear drug effect (Emax) model. (A) The maximum of moving average concentration over 18 days, max(Cavg,18day), turns out to be a good predictor of Topotecan induced median ANC nadir(R2 = 0.79, p<0.01). While in case of Etoposide the maximum of moving average concentration below threshold over 16 days i.e IC50, max(Cavg,16day<IC50), shows maximum ability to predict Etoposide induced median ANC nadir across total dose and schedules(R2 = 0.84, p<0.01).
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pone-0109892-g004: Consistency of moving average of PK in describing severity of neutropenia across drugs.The maximum of the moving average concentration over the dosing interval was examined for its consistency to predict neutropenia across different drugs. Topotecan induced neutropenia was simulated using linear drug effect model while in case of Etoposide, simulation was carried out using nonlinear drug effect (Emax) model. (A) The maximum of moving average concentration over 18 days, max(Cavg,18day), turns out to be a good predictor of Topotecan induced median ANC nadir(R2 = 0.79, p<0.01). While in case of Etoposide the maximum of moving average concentration below threshold over 16 days i.e IC50, max(Cavg,16day<IC50), shows maximum ability to predict Etoposide induced median ANC nadir across total dose and schedules(R2 = 0.84, p<0.01).

Mentions: Having identified a PK parameter, max(cavg,16days), that highly correlates with the severity of neutropenia induced by docetaxel, we then sought to demonstrate that this parameter was an intrinsic property of the neutrophil system and not specific to docetaxel. The analysis was therefore extended to include both etoposide and topotecan (Figures S1, S2, and S3). To test if the moving average concentration, max(cavg,16days), is a property of the neutrophil system alone, we tested if this parameter was a good predictor independent of the drug inducing the neutropenia. For topotecan, which has a linear drug-effect model [26], [34], the moving average of concentration is strongly predictive for ANC nadir (R2 = 0.79, p<0.01; Figure 4a and Figure S1). On the other hand, compared to clinically relevant plasma exposures, etoposide was found to have a highly nonlinear relationship between drug concentration and effect on the stem cell compartment [26], [34]. To account for the nonlinearity, we therefore used the moving average of concentration below IC50 of the drug (see methods) and the moving average of this parameter again is strongly predictive (R2 = 0.84, p<0.01; Figure 4b and Figure S2).


Dose schedule optimization and the pharmacokinetic driver of neutropenia.

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

Consistency of moving average of PK in describing severity of neutropenia across drugs.The maximum of the moving average concentration over the dosing interval was examined for its consistency to predict neutropenia across different drugs. Topotecan induced neutropenia was simulated using linear drug effect model while in case of Etoposide, simulation was carried out using nonlinear drug effect (Emax) model. (A) The maximum of moving average concentration over 18 days, max(Cavg,18day), turns out to be a good predictor of Topotecan induced median ANC nadir(R2 = 0.79, p<0.01). While in case of Etoposide the maximum of moving average concentration below threshold over 16 days i.e IC50, max(Cavg,16day<IC50), shows maximum ability to predict Etoposide induced median ANC nadir across total dose and schedules(R2 = 0.84, p<0.01).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4215876&req=5

pone-0109892-g004: Consistency of moving average of PK in describing severity of neutropenia across drugs.The maximum of the moving average concentration over the dosing interval was examined for its consistency to predict neutropenia across different drugs. Topotecan induced neutropenia was simulated using linear drug effect model while in case of Etoposide, simulation was carried out using nonlinear drug effect (Emax) model. (A) The maximum of moving average concentration over 18 days, max(Cavg,18day), turns out to be a good predictor of Topotecan induced median ANC nadir(R2 = 0.79, p<0.01). While in case of Etoposide the maximum of moving average concentration below threshold over 16 days i.e IC50, max(Cavg,16day<IC50), shows maximum ability to predict Etoposide induced median ANC nadir across total dose and schedules(R2 = 0.84, p<0.01).
Mentions: Having identified a PK parameter, max(cavg,16days), that highly correlates with the severity of neutropenia induced by docetaxel, we then sought to demonstrate that this parameter was an intrinsic property of the neutrophil system and not specific to docetaxel. The analysis was therefore extended to include both etoposide and topotecan (Figures S1, S2, and S3). To test if the moving average concentration, max(cavg,16days), is a property of the neutrophil system alone, we tested if this parameter was a good predictor independent of the drug inducing the neutropenia. For topotecan, which has a linear drug-effect model [26], [34], the moving average of concentration is strongly predictive for ANC nadir (R2 = 0.79, p<0.01; Figure 4a and Figure S1). On the other hand, compared to clinically relevant plasma exposures, etoposide was found to have a highly nonlinear relationship between drug concentration and effect on the stem cell compartment [26], [34]. To account for the nonlinearity, we therefore used the moving average of concentration below IC50 of the drug (see methods) and the moving average of this parameter again is strongly predictive (R2 = 0.84, p<0.01; Figure 4b and Figure S2).

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