Mechanistic mathematical modelling of granulopoiesis: Elucidating the negative feedback interactions between G-CSF and neutrophils and the physiological determinants of G-CSF pharmacokinetics

Morgan Craig
Program for Evolutionary Dynamics, Harvard University, Cambridge

Pharmacokinetic (PK) models describing the disposition of drugs within the body are generally constructed from surrogate data using a variety of methods. Unfortunately, traditional PK models are largely absent of the mechanisms driving drug interactions. Worse, in some cases, the classic PK modelling approach can lead to erroneous conclusions about the physiological system at hand. In this talk, I will focus on the development of a physiological model of the production of neutrophils in the bone marrow. The model is a set of delay differential equations (DDEs) with state-dependent delays and a variable maturation rate, constructed directly from the physiology of the hematopoietic system.
The process of producing a neutrophil is mediated by the endogenous cytokine granulocyte colony-stimulating factor (G-CSF), whose PKs are dictated by the negative feedback interactions between G-CSF and the neutrophil lineage. Here, I will detail the determination of a novel PK model of G-CSF using the DDE physiological model as a basis, and show how traditional PK approaches have previously mischaracterised the elimination kinetics of G-CSF. I will also touch on how, due to its careful construction from the mechanisms of the blood system, the combined model can be applied to answer fundamental physiological questions, and discuss future directions.