title: Characterization of endogenous G-CSF and the inverse correlation to chemotherapy-induced neutropenia in patients with breast cancer using population modeling.
abstract: OBJECTIVE
  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 · 10(9)/L to the total G-CSF elimination.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden, angelica.quartino@gmail.com.
authors.forename: Angelica L
authors.initials: AL
authors.lastname: Quartino
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Lindman
authors.forename: Lena E
authors.initials: LE
authors.lastname: Friberg
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015251:Epirubicin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced*; D009504:Neutrophils; D011446:Prospective Studies
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil