Model of chemotherapy-induced myelosuppression with parameter consistency across drugs

J Clin Oncol. 2002 Dec 15;20(24):4713-21. doi: 10.1200/JCO.2002.02.140.


Purpose: To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs.

Patients and methods: Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software.

Results: For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs.

Conclusion: This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bone Marrow / drug effects*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Docetaxel
  • Etoposide / pharmacology
  • Humans
  • Irinotecan
  • Leukocytes / drug effects
  • Models, Biological*
  • Neutrophils / drug effects
  • Paclitaxel / analogs & derivatives*
  • Paclitaxel / pharmacology
  • Taxoids*
  • Vinblastine / analogs & derivatives*
  • Vinblastine / pharmacology


  • Antineoplastic Agents
  • Taxoids
  • Deoxycytidine
  • Docetaxel
  • vinflunine
  • Vinblastine
  • Etoposide
  • Irinotecan
  • 2'-deoxy-2'-methylenecytidine
  • Paclitaxel
  • Camptothecin