Pharmacodynamic Age Structured Population Model For Cell Trafficking

Area of Science:

• Pharmacometrics
• Immunology
• Mathematical Modeling

Background:

• Cell trafficking is crucial for immune system function, involving immune cell movement between blood and tissues.
• Corticosteroids are known to suppress immune cell trafficking, impacting immune responses.
• Age-structured models quantify immune cell transit times in blood and extravascular tissues.

Purpose of the Study:

• To develop an age-structured cell population model for quantifying drug effects on cell trafficking.
• To implement this model in pharmacometric software for parameter estimation and simulations.
• To investigate the impact of drug-induced changes in cell trafficking on immune cell dynamics.

Main Methods:

• Adopted the McKendrick age-structured population model for blood and extravascular cell populations.
• Modeled age-dependent cell recirculation using a Weibull function.
• Incorporated drug effects on cell trafficking via an Emax function of plasma concentration, implemented in NONMEM.

Main Results:

• The age structure was essential for explaining the rebound in blood cell counts post-drug administration (ν >1).
• Model parameter estimates included ν=3.02, β=0.00863 1/h, and IC50=7.47 ng/mL.
• Calculated baseline mean transit times for basophils were 7.2 h (blood) and 104.9 h (extravascular tissues).

Conclusions:

• An age-structured population model was developed to describe drug-modulated cell trafficking between blood and tissues.
• The model successfully accounted for inhibitory drug effects on cell recirculation.
• The model's ability to explain rebound phenomena was validated using basophil responses to dexamethasone treatment.