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Characterization of Endogenous G-CSF and the Inverse Correlation to Chemotherapy-Induced Neutropenia in Patients with Breast Cancer Using Population Modeling

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Abstract

Purpose

Neutropenia is a severe adverse-event of chemotherapeutics. Neutrophils (ANC) are mainly regulated by granulocyte colony stimulating factor (G-CSF). The aim was to characterize the dynamics between endogenous G-CSF and ANC over time following chemotherapy.

Methods

Endogenous G-CSF and ANC were monitored in forty-nine breast cancer patients treated with sequential adjuvant 5-fluorouracil–epirubicin–cyclophosphamide and docetaxel.

Results

During treatment courses ANC was transiently decreased and was reflected in an endogenous G-CSF increase, which was well described by a semi-mechanistic model including control mechanisms; when G-CSF concentrations increased the proliferation rate increased and the bone maturation time reduced for ANC. Subsequently, ANC in the circulation increased leading to increased elimination of G-CSF. Additionally, a non-specific elimination for G-CSF was quantified. The ANC-dependent elimination contributed to 97% at baseline and 49% at an ANC of 0.1 · 109/L to the total G-CSF elimination.

Conclusion

The integrated G-CSF–myelosuppression model captured the initial rise in endogenous G-CSF following chemotherapy-induced neutropenia and the return to baseline of G-CSF and ANC. The model supported the self-regulatory properties of the system and may be a useful tool for further characterization of the biological system and in optimization of chemotherapy treatment.

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Abbreviations

AAG:

Alpha-1 acid glycoprotein

ALB:

Albumin

ALT:

Alanine aminotransferase

ANC:

Absolute neutrophil count

ANC0 :

Baseline neutrophil count

AP:

Alkaline phosphate

AST:

Aspartate aminotransferase

BSA:

Body surface area

BSV:

Between subject variability

CLCR :

Creatinine clearance

CRP:

C-reactive protein

CV%:

Coefficient of variation

DOSEcort :

Amount of cortisol-induced G-CSF release

FEC:

5-flourouracil-epirubicin-cyclophosphamide

FOCE:

First-order conditional estimation method

G-CSF:

Granulocyte colony stimulating factor

GCSF0 :

Baseline G-CSF

IL-6:

Interleukin 6

kANC :

ANC-dependent elimination rate constant

ke :

Non-specific elimination rate constant

MMT:

Mean bone marrow maturation time of neutrophils

MMTFEC :

Mean bone marrow maturation time of neutrophils following FEC treatment

OFV:

Objective function value

PK:

Pharmacokinetics

PKPD:

Pharmacokinetic-pharmacodynamic

rh-GCSF:

Recombinant G-CSF

RSE:

Relative standard error

SLOPE5-FU :

Linear drug effect parameters for 5-FU

SLOPEcyclo :

Linear drug effect parameters for 4-hydroxy cyclophosphamide

SLOPEdoce :

Linear drug effect parameters for docetaxel

SLOPEepi, :

Linear drug effect parameters for epirubicin

t1/2 circ:

Half-life of neutrophils in circulation

t1/2 cort:

Half-life of cortisol-induced G-CSF release

VPC:

Visual predictive check

4-OHCP:

4-hydroxy cyclophosphamide

5-FU:

5-flourouracil

β:

Feedback of G-CSF on transit time

γ:

Feedback of G-CSF on neutrophil proliferation

θMMT-doce :

Change in MMT following docetaxel compared to FEC

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ACKNOWLEDGMENTS AND DISCLOSURES

We are grateful to all the patients who kindly participated in the study. We also like to thank Anders Larsson, Åsa Hedlund and Jessica Barrefjord for technical assistance. Model estimation was in part performed on resources provided by Swedish National Infrastructure for Computing (SNIC) through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX). Martin Agback at UPPMAX is acknowledged for assistance concerning technical aspects in making NONMEM run on the UPPMAX resources. The study was supported by the Swedish Cancer Society.

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Authors and Affiliations

  1. The Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden

    Angelica L. Quartino, Mats O. Karlsson & Lena E. Friberg

  2. Department of Oncology, Uppsala University Hospital, Uppsala, Sweden

    Henrik Lindman

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  1. Angelica L. Quartino
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  2. Mats O. Karlsson
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Correspondence to Angelica L. Quartino.

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Quartino, A.L., Karlsson, M.O., Lindman, H. et al. Characterization of Endogenous G-CSF and the Inverse Correlation to Chemotherapy-Induced Neutropenia in Patients with Breast Cancer Using Population Modeling. Pharm Res 31, 3390–3403 (2014). https://doi.org/10.1007/s11095-014-1429-9

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