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Characterizing Intentional and Unintentional Drug-Drug Interactions to Improve the Pharmacokinetics of Ibrutinib and Venetoclax

Eisenmann, Eric Daniel
http://orcid.org/0000-0003-1176-675X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1638130062920909

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Targeted therapies have transformed the modern landscape of cancer therapy. Despite improving outcomes in several types of cancer and their ostensible selectivity, many targeted drugs, including ibrutinib and venetoclax, have limited oral bioavailability and highly variable pharmacokinetics that could contribute to the development of severe adverse effects. Here, we discuss mechanisms that limit oral bioavailability and how drugs may impact, or be impacted by, these pathways. We highlight the implications of both unintentional and intentional drug-drug interactions (Chapter 1). We then unequivocally demonstrate that CYP3A limits ibrutinib bioavailability by using genetically engineered mouse models. We illustrate that pharmacologic inhibition of CYP3A with cobicistat is feasible to improve ibrutinib bioavailability without impacting anticancer activity (Chapter 2). Finally, we characterize the mechanisms underlying drug-drug interactions between venetoclax and clinically-relevant antifungal drugs, including identifying OATP1B1 as a potential contributor (Chapter 3). Results from these studies support the future clinical evaluation of strategies to improve the pharmacokinetics of each of these drugs (Chapter 4).
Sharyn Baker (Advisor)
Alex Sparreboom (Committee Member)
Christopher Coss (Committee Member)
Jennifer Woyach (Committee Member)
155 p.
Biomedical Research; Medicine; Pharmaceuticals; Pharmacology; Pharmacy Sciences
Targeted chemotherapeutics; drug disposition; ibrutinib; venetoclax; drug metabolizing enzymes; drug transporters; boosting

Recommended Citations

Citations

  • Eisenmann, E. D. (2021). Characterizing Intentional and Unintentional Drug-Drug Interactions to Improve the Pharmacokinetics of Ibrutinib and Venetoclax [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1638130062920909

    APA Style (7th edition)

  • Eisenmann, Eric. Characterizing Intentional and Unintentional Drug-Drug Interactions to Improve the Pharmacokinetics of Ibrutinib and Venetoclax. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1638130062920909.

    MLA Style (8th edition)

  • Eisenmann, Eric. "Characterizing Intentional and Unintentional Drug-Drug Interactions to Improve the Pharmacokinetics of Ibrutinib and Venetoclax." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1638130062920909

    Chicago Manual of Style (17th edition)

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© 2021, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.