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

    loading  Checking for direct PDF access through Ovid



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.


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.


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 µg · 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).


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

Related Topics

    loading  Loading Related Articles