Pharmacodynamic models of age-structured cell populations.

The purpose of this work is to review basic pharmacodynamic (PD) models describing drug effects on cell populations and expand them to age-structured models using the theory of physiologically structured populations. The plasma drug concentrations are interpreted as the environment affecting the cell production and mortality rates. An explicit solution to model equations provides the age density distribution that serves to establish a relationship between the cell lifespan distribution and the hazard of cell removal. Given the lifespan distributions, the age distributions for most commonly applied PD models of cell responses including basic cell turnover, transit compartments, and basic lifespan models have been derived both for the baseline conditions and drug treatment. The steady-state age distribution for basic indirect response models is exponential, and it is uniform for the basic lifespan model. As an example of more complex cell population, the age distribution of human red blood cells has been simulated based on a recent model of red blood cell survival. The age distribution for cells in the transit compartment model is the sum of the gamma functions. Means and variances of age distributions for all discussed models were calculated. A brief discussion of numerical challenges and possible future model developments is presented.