Neutrophil dynamics after chemotherapy and G-CSF: the role of pharmacokinetics in shaping the response

Abstract

Chemotherapy has profound effects on the hematopoietic system, most notably leading to neutropenia. Granulocyte colony stimulating factor (G-CSF) is often used to deal with this neutropenia, but the response is highly variable. In this paper we examine the role of pharmacokinetics and delivery protocols in shaping the neutrophil responses to chemotherapy and G-CSF. Neutrophil responses to different protocols of chemotherapy administration with varying dosages, infusion times, and schedules are studied through a mathematical model. We find that a single dose of chemotherapy produces a damped oscillation in neutrophil levels, and short-term applications of chemotherapy can induce permanent oscillations in neutrophil level if there is a bistability in the system. In addition, we confirm previous findings [Zhuge et al., J. Theor. Biol., 293(2012), 111-120] that when periodic chemotherapy is given, there is a significant period of delivery that induces resonance in the system and exacerbates the corresponding neutropenia. The width of this resonant period peak increases with the recovery rate after a single chemotherapy, which is given by the real part of the dominant eigenvalue pair at the steady state, and both are determined by a single cooperativity coefficient in the feedback function for the neutrophils. Our numerical studies show that the neutropenia caused by chemotherapy can be overcome if G-CSF is given early after chemotherapy but can actually be worsened if G-CSF is given later, consistent with results reported in Zhuge et al. (2012). The nadir in neutrophil level is found to be more sensitive to the dosage of chemotherapy than that of the G-CSF. Furthermore, dependence of our results with changes in key pharmacokinetic parameters as well as initial functions are studied. Thus, this study illuminates the potential for destructive resonance leading to neutropenia in response to periodic chemotherapy, and explores and explains why the timing of G-CSF is so crucial for successful reversal of chemotherapy induced neutropenia.