The complex effect of granulocyte colony-stimulating factor on human granulopoiesis analyzed by a new physiologically-based mathematical model

V. Vainstein, Y. Ginosar, M. Shoham, D. O. Ranmar, A. Ianovski, Z. Agur

Research output: Contribution to journalArticlepeer-review

Abstract

Neutropenia, frequently a side effect of chemo- and radiotherapy, increases susceptibility to microbial infections and is a life-threatening condition. For realistically predicting drug treatment effects on granulopoiesis, we have constructed a new mathematical model of granulopoiesis in the bone marrow and in the peripheral blood, featuring cell cycle phase transition and detailed granulocyte-colony stimulating factor (G-CSF) pharmacokinetics (PK) and pharmacodynamics (PD), including intracellular second messenger. Using this model, in conjunction with clinical results, we evaluated the system parameters, implemented those in the model and successfully retrieved the results of several independent clinical experiments under a wide range of G-CSF regimens. Our results show that the introduction of G-CSF-controlled intracellular second messenger is indispensable for precise retrieval of the clinical results, and suggest that the half-life of this messenger varies between a single and multiple G-CSF administration schedules. In addition, our model provided reliable steady-state, as well as dynamic, estimations of human granulopoiesis parameters. These included an estimation of apoptosis index in the post-mitotic compartment, which corroborates previous results. At present the model is used for suggesting improved drug regimens.

Original languageEnglish
Pages (from-to)311-327
Number of pages17
JournalJournal of Theoretical Biology
Volume234
Issue number3
DOIs
StatePublished - 7 Jun 2005

Bibliographical note

Funding Information:
The authors wish to thank Y. Kogan and S. Fleishman for fruitful discussion, and the Chai Foundation for financial support.

Keywords

  • G-CSF
  • Granulopoiesis
  • Mathematical model

ASJC Scopus subject areas

  • General Agricultural and Biological Sciences
  • Applied Mathematics
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • Statistics and Probability
  • Modeling and Simulation

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