Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia

J. G.Coen Van Hasselt; Anubha Gupta; Ziad Hussein; Jos H. Beijnen; Jan H.M. Schellens; Alwin D.R. Huitema

doi:10.1111/bcp.12143

Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia

J. G.Coen Van Hasselt^*, Anubha Gupta, Ziad Hussein, Jos H. Beijnen, Jan H.M. Schellens, Alwin D.R. Huitema

^*Corresponding author for this work

Clinical Pharmacy

Research output: Contribution to journal › Article › Academic › peer-review

19 Citations (Scopus)

Abstract

Aims: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia. Methods: A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. Results: Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC₀) was estimated to be 4.03 × 10⁹neutrophilsl^-1 [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451μgl^-1 (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time. Conclusions: The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

Original language	English
Pages (from-to)	412-424
Number of pages	13
Journal	British Journal of Clinical Pharmacology
Volume	76
Issue number	3
DOIs	https://doi.org/10.1111/bcp.12143
Publication status	Published - 1 Sept 2013

Keywords

Eribulin mesilate
Haematological toxicity
Modelling
Neutropenia
NONMEM
Pharmacodynamics

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10.1111/bcp.12143

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@article{6241d8b517fa4d419cc0051b73cb67b0,

title = "Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia",

abstract = "Aims: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia. Methods: A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. Results: Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 109neutrophilsl-1 [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451μgl-1 (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time. Conclusions: The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.",

keywords = "Eribulin mesilate, Haematological toxicity, Modelling, Neutropenia, NONMEM, Pharmacodynamics",

author = "{Van Hasselt}, {J. G.Coen} and Anubha Gupta and Ziad Hussein and Beijnen, {Jos H.} and Schellens, {Jan H.M.} and Huitema, {Alwin D.R.}",

year = "2013",

month = sep,

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doi = "10.1111/bcp.12143",

language = "English",

volume = "76",

pages = "412--424",

journal = "British Journal of Clinical Pharmacology",

issn = "0306-5251",

publisher = "Wiley-Blackwell",

number = "3",

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TY - JOUR

T1 - Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia

AU - Van Hasselt, J. G.Coen

AU - Gupta, Anubha

AU - Hussein, Ziad

AU - Beijnen, Jos H.

AU - Schellens, Jan H.M.

AU - Huitema, Alwin D.R.

PY - 2013/9/1

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N2 - Aims: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia. Methods: A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. Results: Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 109neutrophilsl-1 [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451μgl-1 (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time. Conclusions: The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

AB - Aims: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia. Methods: A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. Results: Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 109neutrophilsl-1 [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451μgl-1 (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time. Conclusions: The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

KW - Eribulin mesilate

KW - Haematological toxicity

KW - Modelling

KW - Neutropenia

KW - NONMEM

KW - Pharmacodynamics

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EP - 424

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

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ER -

Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia

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