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Please use this identifier to cite or link to this item: http://hdl.handle.net/1860/3459

Title: Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats
Authors: Chen, Wendi
Keywords: Electric engineering;Pharmacokinetics;Pharmacodynamics
Issue Date: 15-Apr-2011
Abstract: Erythropoiesis is a process by which red blood cells are produced in the bone marrow. Disruption of this process can lead to anemia. Erythropoiesis stimulating agents (ESAs), such as epoetin- and darbepoetin- , have been developed to treat anemia. CNTO 530 is a novel ESA that has a longer terminal half-life than either epoetin- or darbepoetin- . As these ESAs all activate erythropoietin receptor (EPO-R), we hypothesize that any di erences in the pharmacologic activity are solely dependent on their pharmacokinetic properties. To test this hypothesis, we proposed a new Pharmacokinetic/Pharmacodynamic (PK/PD) model to account for the pharmacological response. Rats received a single subcutaneous (s.c.) dose of the ESA and reticulocyte (RET) counts, red blood cell (RBC) counts and hemoglobin (HGB) levels were measured for up to 72 days (1728 hours) post-dosing. Various dosage levels were studied for each drug. A new indirect response model with multiple regulatory e ects was used to characterize the PD responses and a linear two-compartmental model was used to characterize the PK responses. All three agents caused a dose responsive increase in RET, RBC and HGB. Compared to epoetin- and darbepoetin- , CNTO 530 caused a longer-lived increase in these parameters. A single PK/PD model could represent all three agents. However, when comparing among the erythropoietic responses to doses that increased RBC, the coe cients of the model indicate that despite having a lower potency, CNTO 530 caused a more rapid mobilization of RET. The results of the PK/PD modeling suggest that CNTO 530 stimulates erythropoiesis in a similar fashion to epoetin- and darbepoetin- and that the PK properties of an ESA are the most important factor in determining e cacy. In addition, dose threshold is an important factor we need to consider in designing the PK/PD model. Understanding dose threshold of a drug aids in determining appropriate dose levels and, therefore, helps diminish side e ects of the compound and reduces treatment costs. Many studies have focused on non-quantitative analysis of drug dose threshold, which can be biased by various factors. Aiming for quantitative analysis of this parameter, we proposed two statistical methods to determine dose threshold of a drug and applied them to CNTO 530.
URI: http://hdl.handle.net/1860/3459
Appears in Collections:Drexel Theses and Dissertations

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