Indirect-response model for the time course of leukopenia with anticancer drugs

Clin Pharmacol Ther. 1998 Nov;64(5):511-21. doi: 10.1016/S0009-9236(98)90134-5.


Background: Because both the nadir count and the duration of leukopenia after chemotherapy with anticancer drugs are important, a pharmacodynamic model describing the entire time course of leukopenia is valuable. In this study, a pharmacodynamic model was developed to simulate leukopenia.

Methods: The model was developed with the 3-hour infusion data of paclitaxel. A concentration-time curve of paclitaxel for each patient estimated by a 3-compartment pharmacokinetic model was used as input to the model, which had 2 compartments corresponding to leukocytes in bone marrow and peripheral blood, respectively. Differentiation stages of myeloid cells sensitive to anticancer drugs were assumed, and exposure to a drug during their sensitive period as a function of time was used to inhibit the production of leukocytes in bone marrow. The model was validated by fitting the data of 24-hour infusion of paclitaxel or 14-day infusion of etoposide.

Results: Successful fitting of the leukopenia after a 3-hour infusion of paclitaxel was achieved. The following parameters were estimated: lag-time, 58 +/- 38 (mean +/- SD) hours before the leukocyte count started to decline; exposure giving 50% inhibition of leukocyte production (IC), 12.1 +/- 6.1 microg x h/mL; and sensitive period, 288 +/- 64 hours. These estimations were within physiologic ranges. In validation, leukopenia after 24-hour infusion of paclitaxel or 14-day infusion of etoposide was also explained by the model. Age was significantly negatively correlated with IC of paclitaxel (P = .039).

Conclusions: This mechanistic model describes the time course of leukopenia and may provide a platform for pharmacodynamic analysis of anticancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / blood
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Area Under Curve
  • Drug Administration Schedule
  • Etoposide / administration & dosage
  • Etoposide / adverse effects
  • Etoposide / blood
  • Etoposide / pharmacokinetics*
  • Female
  • Humans
  • Infusions, Intravenous
  • Leukopenia / blood*
  • Leukopenia / chemically induced
  • Male
  • Mathematical Computing
  • Middle Aged
  • Models, Theoretical
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects
  • Paclitaxel / blood
  • Paclitaxel / pharmacokinetics*
  • Time Factors


  • Antineoplastic Agents, Phytogenic
  • Etoposide
  • Paclitaxel