Semi-mechanistic model for neutropenia after high dose of chemotherapy in breast cancer patients

Pharm Res. 2009 Aug;26(8):1952-62. doi: 10.1007/s11095-009-9910-6. Epub 2009 Jun 2.


Purpose: To describe the absolute neutrophil counts (ANC) profile in breast cancer patients receiving high-dose of chemotherapy and peripheral blood stem-cells (PBSC) transplantation.

Methods: Data from 41 subjects receiving cyclophosphamide, thiotepa and carboplatin were used to develop the ANC model consisting of a drug-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments. PBSC were incorporated into the first transit compartment following a zero-order process, k(in), and the rebound effect was explained by a feedback mechanism. A 'kinetics of drug action' model was used to quantify the HDC effect on the progenitor cells according to a linear function, with a slope (alpha).

Results: The typical of the ANC at baseline (Circ(0)), mean transit time (MTT), feedback parameter (gamma), k(in) and alpha were estimated to be 5,610 x 10(6)/L, 3.25 days, 0.145, 0.954 cell/kg/day and 2.50 h/U, respectively. rHuG-CSF shortens the MTT by 92% and increases the mitotic activity by 120%. Bootstrap analysis, visual predictive check and numerical predictive checks evidenced accurate prediction of the ANC nadir, time to ANC nadir and time to grade 4 neutropenia recovery.

Conclusion: The time course of neutropenia following high-dose of chemotherapy and PBSC transplantation was accurately predicted. Higher amount of CD34+ cells in the PBSC transplantation and earlier administration rHuG-CSF were associated with faster haematological recovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / blood
  • Breast Neoplasms / complications
  • Breast Neoplasms / drug therapy*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Middle Aged
  • Models, Biological*
  • Neutropenia / chemically induced*


  • Antineoplastic Agents