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Pharmacokinetics, pharmacodynamics and metabolism of GTI-2040, a phosphorothioate oligonucleotide targeting R2 subunit of ribonucleotide reductase

Wei, Xiaohui
http://rave.ohiolink.edu/etdc/view?acc_num=osu1143220921

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Pharmacy.
Over the last several decades, antisense therapy has been developed into a promising gene-targeted strategy to specifically inhibit the gene expression. Ribonucleotide reductase (RNR), composing of subunits R1 and R2, is an important enzyme involved in the synthesis of all of the precursors used in DNA replication. Over-expression of R2 has been found in almost every type of cancer studied. GTI-2040 is a 20-mer phosphorothioate oligonucleotide targeting the coding region in mRNA of the R2 component of human RNR. In this project, clinical pharamcokinetics (PK), pharmacodynamics (PD) and metabolism of this novel therapeutics were investigated in patients with acute myeloid leukemia (AML). A picomolar specific hybridization-ligation ELISA method has been developed and validated for quantification of GTI-2040. GTI-2040 and neophectin complex was found to enhance drug cellular uptake and exhibited sequence- and dose-dependent down-regulation of R2 mRNA and protein in K562 cells. Robust intracellular concentrations (ICs) of GTI-2040 were achieved in peripheral blood mononuclear cells (PBMC) and bone marrow (BM) cells from treated AML patients. GTI-2040 concentrations in the nucleus of BM cells were found to correlate with the R2 mRNA down-regulation and disease response. In treated patients from 18-60 years old, down-regulations of R2 protein were found in responders, while the non-responders were found to exhibit up-regulation of R2 proteins. Plasma PK of GTI-2040 in AML patients were characterized and found to fit a two-compartment infusion model with mean body clearance of 10.1 L/hr, mean t1/2á of 0.81 hr and mean t 1/2â of 27 hr. Population PK analysis of GTI-2040 identified BM cellularity, white blood cell counts and gender to be important covariates of PK parameters. A PK/PD model has been developed to characterize the dynamics of down-regulation of R2 mRNA following drug perturbation. The 3’ end chain-shortened metabolites of GTI-2040 were identified in various specimens from human and animals using a novel ion-pair reverse-phase high performance liquid chromatography/mass spectrometry (HPLC/MS) method. Sequential metabolism and protein binding were found to complicate the enzyme kinetics of GTI-2040 in human liver microsomes. The results from these studies provided valuable insights to the evaluation and utilization of GTI-2040 in the clinics.
Kenneth Chan (Advisor)
331 p.
Health Sciences, Pharmacy
Pharmacokinetics; Pharmacodynamics; Metabolism; Antisense Oligonucleotides

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Citations

  • Wei, X. (2006). Pharmacokinetics, pharmacodynamics and metabolism of GTI-2040, a phosphorothioate oligonucleotide targeting R2 subunit of ribonucleotide reductase [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1143220921

    APA Style (7th edition)

  • Wei, Xiaohui. Pharmacokinetics, pharmacodynamics and metabolism of GTI-2040, a phosphorothioate oligonucleotide targeting R2 subunit of ribonucleotide reductase. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1143220921.

    MLA Style (8th edition)

  • Wei, Xiaohui. "Pharmacokinetics, pharmacodynamics and metabolism of GTI-2040, a phosphorothioate oligonucleotide targeting R2 subunit of ribonucleotide reductase." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1143220921

    Chicago Manual of Style (17th edition)

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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.