Many pharmacodynamic (PD) models of cellular response assume a single and time invariant lifespan of all cells, despite the existence of a true underlying distribution of cellular lifespans and known changes in the lifespan distributions with time. To account for these features of cellular populations, a time variant cellular lifespan distribution PD model was formulated and theoretical aspects of modeling cellular populations presented. The model extends prior work assuming time variant “point distributions” of cellular lifespans (Freise et al. J Pharmacokinet Pharmacodyn 34:519–547, 2007) and models assuming a time invariant lifespan distribution (Krzyzanski et al. J Pharmacokinet Pharmacodyn 33:125–166, 2006). The formulated time variant lifespan distribution model was fitted to endogenous plasma erythropoietin (EPO), reticulocyte, and red blood cell (RBC) concentrations in sheep phlebotomized on two occasions, 8 days apart. The time variant circulating reticulocyte lifespan was modeled as a truncated and scaled Weibull distribution, with the location parameter of the distribution non-parametrically represented by an end constrained quadratic spline function. The formulated time variant lifespan distribution model was compared to the identical time invariant distribution, time variant “point distribution”, and time invariant “point distribution” cellular lifespan models. Parameters of the time variant lifespan distribution model were well estimated with low standard errors. The mean circulating reticulocyte lifespan was estimated at 0.304 days, which rapidly increased over 3-fold following the first phlebotomy to a maximum of 1.03 days (P = 0.009). On average, the percentage of erythrocytes being released as reticulocytes maximally increased an estimated two-fold following the phlebotomies. The primary features of immature RBC physiology were captured by the model and gave results consistent with other estimates in sheep and humans. The comparison of the four lifespan models gave similar parameter estimates of the stimulation function and fits to the RBC data. However, the time invariant models fit the reticulocyte data poorly, while the time variant “point distribution” cellular lifespan model gave physiologically unrealistic estimates of the changes in the circulating reticulocyte lifespan under stress erythropoiesis. Thus the underlying physiology must be considered when selecting the most appropriate cellular lifespan model and not just the goodness-of-fit criteria. The proposed PD model and the numerical implementation allows for a flexible framework to incorporate time variant lifespan distributions when modeling populations of cells whose production or stimulation depends on endogenous growth factors and/or exogenous drugs.