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Dissertation
Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2010
DOI:
https://doi.org/10.17918/etd-3459
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-[alpha] and darbepoetin-[alpha], have been developed to treat anemia. CNTO 530 is a novel ESA that has a longer terminal half-life than either epoetin-[alpha] or darbepoetin-[alpha]. As these ESAs all activate erythropoietin receptor (EPO-R), we hypothesize that any differences 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 effects 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-[alpha] and darbepoetin-[alpha], 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 coefficients 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-[alpha] and darbepoetin-[alpha] and that the PK properties of an ESA are the most important factor in determining efficacy. 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 effects 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.
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Details
- Title
- Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats
- Creators
- Wendi Chen - DU
- Contributors
- Leonid Hrebien (Advisor) - Drexel University (1970-)Moshe Kam (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Engineering (1970-2026); Electrical (and Computer) Engineering [Historical]; Drexel University
- Other Identifier
- 3459; 991014632051104721