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Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite

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2011, Doctor of Philosophy, Ohio State University, Pharmacy.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western world. Flavopiridol (Alvocidib, NSC 649890), as a pan cyclin-dependent kinases inhibitor (CDKI), initiates cell cycle arrest and p53-independent apoptosis through down-regulation of Mcl-1 and X-linked inactivator of apoptosis (XIAP). A novel pharmacokinetically (PK)-based dosing schedule with a 30-minute intravenous bolus loading dose (IVB) followed by a 4-hour continuous intravenous infusion (CIVI) in patients with refractory CLL produced an approximately 50% overall response rate. A major flavopiridol metabolite, flavopiridol glucuronide (flavo-G), was as also evaluated in this study. In order to fully understand the inter-individual variability between patients, a phase 1 CLL patient data set (OSU0055) was evaluated and a two-compartment flavopiridol PK model followed by first-order elimination was developed by nonlinear mixed effects modeling. Bilirubin level was shown as a significant covariate, and OATP1B1 was first time discovered having a significant correlation with flavopiridol PK parameters. A functional analysis in vitro study was done to confirm that flavopiridol and flavo-G are substrates of OATP1B1. Since cellular redox status is important on cell survival and previous studies showed that flavopiridol can induce the decrease of intracellular GSH levels in transformed cells, glutathione (GSH) level was evaluated among leukemia cell models and patient’s CLL cells. The change in GSH level compared to baseline after flavopiridol treatment varied among cell models and individual patient. In order to evaluate flavo-G with flavopiridol treatment, a linked parent-metabolite population PK model was developed. This model was expanded to include a pharmacodynamic logistic-regression component linked to flavopiridol exposure level. This developing PK-PD-PG model of flavopiridol will help to characterize the factors associated with inter-individual variability in drug disposition and outcomes, and provide us better understanding of the mechanisms and factors governing the balance between safety and efficacy.
Mitch A. Phelps, PhD (Committee Chair)
Guillaume Wientjes, PhD (Committee Member)
Robert Lee, PhD (Committee Member)
137 p.

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Citations

  • Ni, W. (2011). Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299680524

    APA Style (7th edition)

  • Ni, Wenjun. Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1299680524.

    MLA Style (8th edition)

  • Ni, Wenjun. "Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299680524

    Chicago Manual of Style (17th edition)