Disposition and dynamics of recombinant human erythropoietin
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Recombinant human erythropoietin (rHuEPO) is an important biologic product that has been widely used to increase formation of red blood cells (RBC) in anemic patients with chronic renal failure and receiving chemotherapy. While its general dispositional properties and effects on erythropoiesis have been long appreciated, the complexities associated with its pharmacokinetics (PK) and pharmacodynamics (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 major goal of this thesis was 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 clinical situations to assist predicting rHuEPO responses under diverse dosing conditions and disease states. Chapter 1 focuses on establishment of a suitable animal model using rats that allowed extensive determinations of PK and PD data simultaneously without disturbing normal physiology. The PK/PD study of rHuEPO conducted in rats after intravenous (i.v.) and subcutaneous (s.c.) administration at various doses was used to construct a comprehensive model that can quantitatively characterize disposition and dynamic effects of rHuEPO on reticulocyte, RBC, and hemoglobin. Time-dependent changes in hematological variables related to growth of rats during the study period were observed and modeled by nonlinear functions. Important questions whether mechanistic models would allow allometric scaling among species were addressed in Chapter 2 . The PK/PD model of rHuEPO was looked at in terms of three components, including PK, pharmacology, and system-related parameters and their correlation to body size were assessed. Most PK parameters and system parameters for RBC and precursor lifespans generally obeyed principles of allometry, but the pharmacologic parameters appeared to be species specific. Chapter 3 summarizes theoretical efforts to extend cell lifespan models from a fixed lifespan to a distribution of lifespans for a given population. The role of lifespan distribution parameters (mean and standard deviation (SD)) in controlling response profiles and estimability of those parameters from data were examined. The second generation model retained major properties of the previous model except for a time-dependent peak time. Simulations indicated that small changes in SD of precursor lifespan distribution may not significantly affect the responses in the central pool and such parameters may not be identified from the final responses unless the precursors were also measured. Hematide, a synthetic dimeric peptide linked to polyethylene glycol (PEG), is under clinical development for treatment of anemia offering extended in vivo erythropoietic activity. Chapter 4 involves the characterization of PK/PD of Hematide in healthy volunteers using NONMEM. A catenary, lifespan-based, indirect response model which was also used to analyze PD responses to rHuEPO reflected the PD of Hematide. The model was used for clinical trial simulations to guide selection of multiple-dosing regimens for treatment of anemic patients with renal failure. Anticancer agents often cause bone marrow toxicity resulting in progressive anemia which may influence the therapeutic effects of rHuEPO. In Chapter 5 , progressive anemia was induced in rats following a single i.v. dose of carboplatin and a physiological PD model was developed in consideration of erythropoiesis and irreversible cell removal process from progenitor cells to describe the time course of anemia. The model also provided a tool to explore the impact of timing of rHuEPO administration relative to bone marrow activity following chemotherapy. While a traditional approach has been successfully applied to describe nonlinear PK of rHuEPO in various species, it does not well represent underlying molecular events such as receptor binding, internalization, and degradation of rHuEPO. In Chapter 6 we evaluated the disposition of rHuEPO over a wide range of doses with a mechanistic PK model delineating the receptor-mediated drug disposition. A generalized form of the model was proposed to characterize the nonlinear kinetic behavior of rHuEPO across species. Furthermore, an integrated receptor-mediated PK/PD model was developed to describe disposition and erythropoietic effects of rHuEPO in rats. This thesis reflects endeavors to integrate PK and PD characteristics of rHuEPO via development of comprehensive PK/PD models. The 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 PK/PD of rHuEPO from rats to humans but were also successfully applied to a new therapeutic agent in humans, demonstrating robustness and great utility to assist drug development processes. Our modeling approach was also expanded to chemotherapy-induced anemia and showed its applicability in selection of a dosing strategy of rHuEPO. These mechanism-based PK/PD models increase our understanding of the complex disposition and erythropoietic effects associated with rHuEPO.