• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Learn & Apply Paradigm to Inform Drug Development & Optimize Clinical Therapeutics in Oncology

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Mehrotra_umaryland_0373D_10818.pdf
    Size:
    9.376Mb
    Format:
    PDF
    Download
    Author
    Mehrotra, Shailly
    Advisor
    Gobburu, Jogarao
    Date
    2017
    Type
    dissertation
    
    Metadata
    Show full item record
    Other Titles
    Learn and Apply Paradigm to Inform Drug Development and Optimize Clinical Therapeutics in Oncology
    Abstract
    Application of learn-apply paradigm in drug development and clinical therapeutics increases efficiency and supports decision making. The current research highlights the role of pharmacometrics to inform trial design and propose individualized management of chemotherapy induced peripheral neuropathy (CIPN) in oncology. The first project focuses on learning from early clinical trial of veliparib to inform future investigations. Population pharmacokinetics and exposure-response analyses were conducted to evaluate the contribution of intrinsic and extrinsic factors on veliparib PK, and assess the adequacy of veliparib dosing for the future trial. A 28% increase in AUC with mild renal impairment increases mucositis by only 7%, thus supporting the inclusion of patients with mild renal impairment in future trials without the need of dose adjustment. Exposure-response for efficacy (objective response rate and overall survival) and safety (mucositis) along with in vitro IC50 information supported 80 mg BID dose for veliparib. Multivariate exposure-response analysis provided supportive evidence to further evaluate veliparib in patients with myeloproliferative neoplasms and with 14 day treatment duration. The second project proposes a novel strategy based on precision therapeutics for the management of CIPN in clinical setting. An indirect response model with linear drug effect was able to describe the longitudinal-CIPN data reasonably well for paclitaxel, nab-paclitaxel and ixabepilone. The model was utilized to identify an early time point of 3 months that predicted later time course of CIPN (concordance probability ~ 75%). Utilizing the dose-CIPN model, a novel strategy to use patients own early CIPN data to predict their future CIPN time course was proposed. 'CIPN management dosing card' and 'CIPN precision therapeutics tool' were developed to prospectively manage CIPN in patients who may be at risk of developing CIPN later in the therapy. For paclitaxel, nab-paclitaxel and ixabepilone, the proposed CIPN management dosing card resulted in 61%, 48% and 35% fewer patients with CIPN after 6 cycles as compared to administering cycle 3 doses for 4th, 5th and 6th chemotherapy cycle. With CIPN precision therapeutics tool, oncologists can visualize the predicted CIPN time course and tailor the dosing to manage CIPN in an individual patient based on overall benefit/risk.
    Description
    University of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 2017
    Keyword
    learn-apply paradigm
    pharmacometrics
    Clinical Trials as Topic
    Data Collection--methods
    Drug Evaluation--methods
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/6745
    Collections
    Theses and Dissertations School of Pharmacy
    Theses and Dissertations All Schools

    entitlement

     
    DSpace software (copyright © 2002 - 2021)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.