A biomathematical model of hematotoxicity

Abstract

Pharmacodynamic models representing interactions among chemicals and cells can help to clarify how time patterns of administered dose affect risks of adverse health outcomes. This paper summarizes a model that predicts the effects of the myelotoxic and immunosuppressive drug cyclophosphamide (CP) on the hematopoietic (blood-forming) system. It consists of a set of physiological compartments representing hematopoietic progenitor cell, granulocyte-macrophage (GM)-committed stem cells, and more mature blood cells. These compartments are linked by nonlinear feedback control loops and are susceptible to first-order cell-killing kinetics from cytotoxic metabolites. The model was validated by testing its predictions against experimental and clinical data for blood cell counts following administration of CP to mice, dogs, and humans. It successfully explains apparent anomalies and patterns in previously published data, including the fact that smaller cumulative doses can cause larger hematotoxic responses. An intriguing prediction from the model is that sustained exposures to sufficiently small concentrations of myelotoxic agents may tend to provoke a protective response, increasing rather than decreasing the numbers of GM colony-forming units (CFU-GM) and early hematopoietic stem cells available to sustain hematopoiesis.