Pharmacodynamic Age Structured Population Model For Cell Trafficking

Abstract

Objectives

Cell trafficking encompasses movement of the immune system cells (e.g., granulocytes, lymphocytes) between the blood and the extravascular tissues (e.g., lymph nodes). Corticosteroids are known to suppress cell trafficking. The age-structured cell population models introduce the transit time as a structure that allows one to quantify the distribution of times the immune cells spend in the blood and the extravascular tissues. The objective of this work is to develop an age-structured cell population model describing drug effects on cell trafficking and to implement the model in pharmacometric software to enable parameter estimation and simulations.

Methods

We adopted the well-known McKendrick age-structured population model to describe the age distributions in two cell populations: blood cells and cells in the extravascular space. The hazard of cell recirculation from the extravascular tissues was age dependent and described by the Weibull function with the shape ν and scale β parameters. The drug effect on cell trafficking was modeled as the product of the Emax function of the drug plasma concentration and the Weibull hazard. The model was implemented in NONMEM 7.5.1. The model was applied to the basophil data in 34 healthy subjects who received a single intramuscular or oral dose of 6 mg dexamethasone (DEX). A recently published pharmacokinetic model was applied to describe DEX plasma concentration. Typical values of parameter estimates were further used to simulate the DEX effect of the basophil mean transit time in the extravascular tissues.

Results

Simulations of basophil time courses for varying ν demonstrated that the rebound in the blood count data following drug administration is only possible for ν >1. The estimates of model parameters were ν = 3.02, β = 0.00863 1/h, and IC₅₀ = 7.47 ng/mL. The calculated baseline mean transit times of basophils in the blood 7.2 h and extravascular tissues 104.9 h agree with the values reported in the literature.

Conclusions

We introduced an age-structured population model to describe cell trafficking between the blood and extravascular tissues. The model was adopted to account for the inhibitory drug effect on the cell recirculation. We showed that the age structure is essential to explain the rebound observed in the blood count response to a single dose drug administration. The model was validated using the basophil responses to DEX treatment in healthy subjects.