Using Mechanistic Modelling of Cyclic Neutropenia to Predict the Effects of a COPD Therapeutic on Systemic Neutrophil Levels
Mark Penney* (1), Sophie Stevens (2)
(1) AstraZeneca Pharmaceuticals plc, Loughborough, UK; (2) Loughborough High School, Loughborough, UK.
Objectives: AZD002 is being developed for the treatment of Chronic Obstructive Pulmonary Disease (COPD). In healthy volunteers it has been shown to cause a dose-dependent reduction in the blood neutrophil count that reverses on the cessation of dosing. Low blood neutrophil counts which are observed in a condition known as cyclic neutropenia or which can be induced by certain chemotherapies are associated with an increased risk of infection and it is therefore important to determine whether there is potential for a similar risk with AZD002.
Methods: As part of this assessment we present a mathematical model based on an existing model of cyclic neutropenia, but which has been extended with the addition of a compartment for mature neutrophils, an implementation of the effect of challenging healthy volunteers with the immune response stimulant lipopolysaccharide (LPS) and with the mechanism of action and PK/PD of AZD002.
Results: Simulating the effects of both LPS and AZD002 together would produce distinct results depending on whether we assume that the LPS-driven rise in blood neutrophil counts is inhibited by, or occurs independently of, AZD002. Only the scenario where the LPS effect is independent of AZD002 is consistent with clinical observations (observed in a trial with AZD001). Moreover, the model predicts that the response to LPS challenge is sub-normal in cyclic neutropenia patients during their neutropenic phase.
Conclusions: Taking both results together predicts a key difference between the mechanisms that cause suppressed blood neutrophil counts in cyclic neutropenia and those induced by AZD002.
 C. Colijn and MC. Mackey, A mathematical model of hematopoiesis, Journal of Theoretical Biology 237:133-146; 2005.