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PhD_Dissertation____King.pdf (14.49 MB)

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Integrated Pharmacokinetic and Pharmacodynamic Modeling in Drug Resistance: Insights From Novel Computational and Experimental Approaches

King, Eshan Spencer
http://orcid.org/0000-0002-0345-3780
http://rave.ohiolink.edu/etdc/view?acc_num=case1717694055606691

Abstract Details

2024, Doctor of Philosophy, Case Western Reserve University, Nutrition.
Drug resistance in both cancer and infectious disease is a major driver of mortality across the globe. In infectious disease, the emergence of antimicrobial resistance (AMR) outpaces our ability to develop novel drugs, and within-host evolution confounds the use of previously effective drugs during the course of treatment. In cancer, while targeted therapies have improved outcomes for some, many patients continue to face metastatic, drug-resistant disease, with limited therapeutic options available. As both disease types are driven by clonal evolution, a complementary approach to treatment that leverages tools and ideas from evolutionary biology has been beneficial. However, this evolutionary-inspired therapy has thus far been limited in its consideration of drug variation in time and space within a patient (pharmacokinetics) and variable pathogen response to drug (pharmacodynamics). In this dissertation, we describe novel computational and experimental approaches that integrate pharmacokinetics and pharmacodynamics to allow for more physically realistic models of the evolution of drug resistance. We apply these approaches to gain novel insights into drug dosing regimens and drug diffusion in tissue. In Chapters 1 and 2, we briefly review integrated pharmacokinetics and pharmacodynamics in the study of drug resistance and survey the current evidence of fitness costs to drug resistance in cancer. In Chapter 3, we developed a novel, fluorescence-based time-kill protocol for estimating drug dose-dependent death rates in bacteria. In Chapter 4, we described a software package, FEArS, that allows for efficient agent-based simulation of evolution under time-varying drug concentration. In Chapter 5, we leverage both of these methods to gain insight into why some antimicrobial treatments fail using computational modeling and simulated clinical pharmacokinetics. In Chapter 6, we use spatial agent-based modeling to examine how drug diffusion in tissue can promote tumor heterogeneity, and how this heterogeneity can contribute to treatment failure. Our work demonstrates how integrated pharmacokinetic and pharmacodynamic modeling can enhance our understanding of drug resistance and potentially guide the development of novel therapeutic strategies in the future.
Mark Chance (Committee Chair)
Christopher McFarland (Committee Member)
Jacob Scott (Advisor)
Michael Hinzcewski (Committee Member)
Drew Adams (Committee Member)
170 p.
Bioinformatics; Biology; Biomedical Research; Biophysics
Drug resistance; systems biology; cancer; infectious disease; bacteria; computational biology; pharmacodynamics; pharmacokinetics; pharmacology

Recommended Citations

Citations

  • King, E. S. (2024). Integrated Pharmacokinetic and Pharmacodynamic Modeling in Drug Resistance: Insights From Novel Computational and Experimental Approaches [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1717694055606691

    APA Style (7th edition)

  • King, Eshan. Integrated Pharmacokinetic and Pharmacodynamic Modeling in Drug Resistance: Insights From Novel Computational and Experimental Approaches. 2024. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1717694055606691.

    MLA Style (8th edition)

  • King, Eshan. "Integrated Pharmacokinetic and Pharmacodynamic Modeling in Drug Resistance: Insights From Novel Computational and Experimental Approaches." Doctoral dissertation, Case Western Reserve University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1717694055606691

    Chicago Manual of Style (17th edition)

case1717694055606691
93
© 2024, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.