Recombinant human erythropoietin (rHuEPO) is an important biologic product that has been widely used to increase formation of red blood cell (RBC) in anemic patients with chronic renal failure and chemotherapy. While its general dispositional properties and effects on erythropoiesis have been long appreciated, the complexities associated with its pharmacokinetics and pharmacodynamics (PK/PD) hampered better clinical use of rHuEPO. Well-designed experiments in preclinical animal models and utilization of mechanism-based PK/PD models can provide better quantitation and prediction of the disposition and dynamics of rHuEPO. The general goals of this study were to develop mechanism-based PK/PD models for rHuEPO that not only can provide improved understanding of disposition and erythropoietic effects of rHuEPO but also can be translated into the clinical situations to assist predicting the responses under diverse dosing conditions and disease states.

            The approaches were to establish a suitable animal model using rats to simultaneously quantify PK and an array of dynamic response variables and to build comprehensive models to describe their relationships. Since erythropoiesis involves a series of differentiation stages from pluripotent hematopoietic stem cell through the mature erythrocyte, an array of hematological changes can be observed following rHuEPO administration. The primary response variables considered included reticulocyte, RBC, and hemoglobin and these variables are quantitatively described by the lifespan-based catenary indirect response model, reflecting the bone marrow and circulating erythropoietic cells. Then important questions whether mechanistic models would allow allometric scaling between species and be relevant for new erythropoiesis-stimulating agents were addressed. Furthermore, the relevance to disease states such as chemotherapy-induced anemia was considered by developing an anemic rat model to study progression of anemia following carboplatin and a PD model to reflect hematotoxicity caused by chemotherapy.  

This study reflects endeavors to integrate PK and PD characteristics of rHuEPO learned over the years from various preclinical and clinical studies of rHuEPO via development of comprehensive PK/PD models. The developed models are mechanistic in nature and closely reflect underlying physiology so that the generalized mechanism-based PK/PD model structures are applicable across species. The models not only quantitatively well described disposition and erythropoietic effects of rHuEPO from rats to humans but were also successfully applied to a new therapeutic analogue of EPO in humans, demonstrating robustness and great utility of the model to assist drug development processes. The current modeling approach was also expanded to chemotherapy-induced anemia and showed its applicability in selection of dosing strategy of rHuEPO. These mechanism-based PK/PD models increase understanding of complex disposition and erythropoietic system associated with rHuEPO.

References

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2.      Woo S and Jusko WJ, Interspecies comparisons of pharmacokinetics and pharmacodynamics of rHuEPO. Drug Metab Dispos 35: 1672-1678 (2007).

3.      Woo S, Krzyzanski W, Duliege A-M, Richard SR, Jusko WJ, Population pharmacokinetic and pharmacodynamic modeling of a novel peptidic erythropoiesis receptor agonist (ERA), Hematide, in healthy volunteers. J Clin Pharmacol 48: 43-52 (2008).

4.      Woo S, Krzyzanski W, Jusko WJ, Pharmacodynamic model for chemotherapy-induced anemia in rats. Cancer Chemother Pharmacol 62: 123-33 (2008).