Multiple-Pool Cell Lifespan Model of Hematologic Effects of Anticancer Agents

Abstract

The leukopenic effects of anticancer agents are described using a semi-physiologic multiple-pool cell lifespan model. The time course of myelosuppression in relation to the drug concentration vs. time profile was characterized using a three pool indirect model. The proliferation and maturation stages of myeloid cells in the bone marrow and cell removal from the circulation were quantitated with a cell life-span concept. Drug effects were assumed to take place in the bone marrow based on irreversible linear or capacity-limited cytotoxicity. Mathematical derivations and computer simulations (Adapt II) were used to examine the properties of the model. Data from the literature were also analyzed. Cell response profiles after therapy typically exhibit a lag period, reduction to a nadir, and return to baseline. The predicted values of the time periods of granulopoiesis were 10–14 days for proliferation, and 1–6 days for maturation of progenitor cells in the bone marrow. The proposed irreversible mechanism of cell killing by anticancer drugs explains previously observed relationships between leukocyte nadir counts and exposure to the drug and/or duration of drug concentrations above some threshold level. The model was applied to literature data for paclitaxel and etoposide effects on leukocyte counts. The predicted value of KC₅₀ for paclitaxel ranged from 0.004 to 0.2 μg/mL and for etoposide 2 μg/mL. The present model accounts for drug-induced leukopenia using a physiologic cell production and loss model and irreversible cytotoxicity in a precursor pool.