Pharmacokinetic–pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer

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Abstract

Aims: The aim of the present study was to develop a pharmacokinetic–pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment. Methods: The study enrolled 17 female patients with stages 1–3 breast cancer and receiving adjuvant doxorubicin (60 mg m–2) and cyclophosphamide (600 mg m–2) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP. Results: A three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8–73.9%). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability. Conclusion: The relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity.

Original languageEnglish (US)
Pages (from-to)773-783
Number of pages11
JournalBritish Journal of Clinical Pharmacology
DOIs
StatePublished - Jan 1 2016

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Brain Natriuretic Peptide
Doxorubicin
Breast Neoplasms
Troponin
Enalapril
Cyclophosphamide
Heart Failure
Parents

Keywords

  • N-terminal pro-brain natriuretic peptide
  • anthracyclines
  • brain natriuretic peptide
  • cardiotoxicity
  • doxorubicin
  • pharmacodynamic modelling

Cite this

@article{ea009d0a3d3749fcbf0859ae3fe7b015,
title = "Pharmacokinetic–pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer",
abstract = "Aims: The aim of the present study was to develop a pharmacokinetic–pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment. Methods: The study enrolled 17 female patients with stages 1–3 breast cancer and receiving adjuvant doxorubicin (60 mg m–2) and cyclophosphamide (600 mg m–2) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP. Results: A three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8–73.9{\%}). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability. Conclusion: The relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity.",
keywords = "N-terminal pro-brain natriuretic peptide, anthracyclines, brain natriuretic peptide, cardiotoxicity, doxorubicin, pharmacodynamic modelling",
author = "Shuang Liang and Richard Brundage and Jacobson, {Pamala A} and Blaes, {Anne H} and Kirstein, {Mark N}",
year = "2016",
month = "1",
day = "1",
doi = "10.1111/bcp.12989",
language = "English (US)",
pages = "773--783",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
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TY - JOUR

T1 - Pharmacokinetic–pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer

AU - Liang, Shuang

AU - Brundage, Richard

AU - Jacobson, Pamala A

AU - Blaes, Anne H

AU - Kirstein, Mark N

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Aims: The aim of the present study was to develop a pharmacokinetic–pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment. Methods: The study enrolled 17 female patients with stages 1–3 breast cancer and receiving adjuvant doxorubicin (60 mg m–2) and cyclophosphamide (600 mg m–2) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP. Results: A three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8–73.9%). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability. Conclusion: The relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity.

AB - Aims: The aim of the present study was to develop a pharmacokinetic–pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment. Methods: The study enrolled 17 female patients with stages 1–3 breast cancer and receiving adjuvant doxorubicin (60 mg m–2) and cyclophosphamide (600 mg m–2) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP. Results: A three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8–73.9%). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability. Conclusion: The relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity.

KW - N-terminal pro-brain natriuretic peptide

KW - anthracyclines

KW - brain natriuretic peptide

KW - cardiotoxicity

KW - doxorubicin

KW - pharmacodynamic modelling

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U2 - 10.1111/bcp.12989

DO - 10.1111/bcp.12989

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JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

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