Dose schedule optimization and the pharmacokinetic driver of neutropenia

PLoS One. 2014 Oct 31;9(10):e109892. doi: 10.1371/journal.pone.0109892. eCollection 2014.


Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacokinetics
  • Docetaxel
  • Drug Administration Schedule*
  • Etoposide / administration & dosage
  • Etoposide / adverse effects
  • Etoposide / pharmacokinetics
  • Humans
  • Male
  • Models, Biological*
  • Models, Theoretical
  • Neutropenia / chemically induced*
  • Rats, Sprague-Dawley
  • Taxoids / administration & dosage
  • Taxoids / adverse effects
  • Taxoids / pharmacokinetics
  • Topotecan / administration & dosage
  • Topotecan / adverse effects
  • Topotecan / pharmacokinetics


  • Antineoplastic Agents
  • Taxoids
  • Docetaxel
  • Etoposide
  • Topotecan

Grants and funding

All authors were employees of Takeda Pharmaceuticals International Co. at the time of these studies and therefore had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.