The disposition of cells whose mechanism of death is related to the age of the cell cannot be appropriately represented by pharmacodynamic (PD) models where the elimination rate is related to the number of cells. In cells with age-related death their disposition is determined by their lifespan. Thus in these cells PD models of cellular response must incorporate a lifespan component. Previous cellular lifespan PD models assumed that the lifespan of cells is predetermined and does not vary over time. However, in many instances these assumptions are inappropriate and thus extensions to the existing models are needed. An important application of these time variant PD models is determining the erythropoiesis rate, since the lifespan of reticulocytes and mature erythrocytes are known to change over time under specific conditions.
The objectives us this work were to develop a general time variant lifespan-based PD model of cellular response and to use the model to determine the dynamic changes over time in both the erythrocyte lifespan and erythropoiesis rate under a variety of complex conditions. An initial time variant cellular lifespan model was formulated assuming no variability in lifespans and used to determine the dynamic changes in both the reticulocyte lifespan and erythropoiesis rate in sheep. Subsequently, the time variant model was extended to account for a distribution of cellular lifespans, which resulted in better capturing the physiology of sheep erythrocyte maturation. The model was then further extended to account for the effect of changes in the environment on cell lifespans and used to determine the effect of chemotherapy administration on sheep erythrocytes. In order to conduct studies on erythropoiesis in premature very low birth weight (VLBW) infants the ability to accurately measure erythrocytes and hemoglobin from clinically collected excess blood was validated. Then an in depth analysis of the relationship between erythropoietin, erythrocytes, and hemoglobin was conducted in a clinical study of premature VLBW infants that accounted for the dynamic hematological conditions experienced by these subjects. This analysis indicated that a nearly 4-fold increase in erythropoiesis could be achieved with only a modest increase in plasma erythropoietin concentrations.