Pharmacodynamic age structured population model for cell trafficking

Cell trafficking encompasses movement of the immune system cells (e.g., granulocytes, lymphocytes) between the blood and the extravascular tissues (e.g., lymph nodes). Basophils are effector cells responsible for inflammatory reactions during the immune challenge. Basophils are used as biomarkers of inflammatory responses. Corticosteroids are known to suppress cell trafficking. Existing models of cell trafficking employ the methodology of compartmental systems where the cells transfer between two compartments at first-order rates. Such an approach limits the model ability to account for prolonged times most of the immune cells spend outside the vasculature before recirculating to the blood. The age-structured population models introduce the transit time as a structure that allows to quantify the distribution of times the immune cells spend in the blood and the extravascular tissues. The key tools are the hazards of transfer between the tissues and hazards of cell death. The hazard can depend on the cell age (e.g., the time it spends in the tissue) and the time (e.g., through the time-dependent drug effect). This webinar will show how to apply the well-known McKendrick age-structured population model to describe drug effects on cell trafficking between blood cells and cells in the extravascular space. The model was validated using published data on corticosteroid inhibition of the basophil counts in healthy volunteers using mixed effects modeling. The corticosteroid effect decreases the hazard of cell recirculation from the extravascular tissues. We will show that the age structure is essential to explain the rebound observed in the blood count response to a single dose drug. We will also provide insights on how to use age-structure population models to describe pharmacodynamics of other cell populations.