Hematological response of topotecan in tumor-bearing rats: modeling of the time course of different cellular populations.

Purpose: To evaluate the hematotoxicity of topotecan (TPT) in tumor-bearing rats by a pharmacokinetic/pharmacodynamic approach.

Methods: DHD/K12-PROb cells were subcutaneously injected in syngenic BD-IX rats. Three weeks after implantation of cells, animals received saline or 6 mg/kg i.p. dose of TPT (group II). Thirty days later, group II was divided into groups IIA receiving a single administration of 6 mg/kg and IIB treated with 3 mg/kg for 2 consecutive days. Leukocytes, neutrophils, and mature lymphocytes were measured in peripheral blood every 48 h for 45 days after first drug administration. Pharmacokinetic characteristics of TPT were also explored.

Results: Disposition of TPT in plasma was best described with a two-compartment model. A semiphysiological model discriminating between system-related and drug-effects parameters, such as the mean cell maturation or transition time (MTT) and the linear concentration-dependent inhibitory effects on cell proliferation (Slp), described adequately the time course of hematotoxicity. The estimates of MTT and Slp for the three cell populations ranged from 1.89 to 2.18 days and from 0.01 to 0.039 ml/ng, respectively.

Conclusion: The time course of the hematotoxicity induced after two cycles of chemotherapy with TPT in tumor-bearing rats could be described by a semiphysiological model.