IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30902-7.html
   My bibliography  Save this article

Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation

Author

Listed:
  • Suyash Deodhar

    (University of Nebraska Medical Center)

  • Brady Sillman

    (University of Nebraska Medical Center
    University of Nebraska Medical Center)

  • Aditya N. Bade

    (University of Nebraska Medical Center)

  • Sean N. Avedissian

    (University of Nebraska Medical Center)

  • Anthony T. Podany

    (University of Nebraska Medical Center)

  • JoEllyn M. McMillan

    (University of Nebraska Medical Center)

  • Nagsen Gautam

    (University of Nebraska Medical Center)

  • Brandon Hanson

    (University of Nebraska Medical Center)

  • Bhagya L. Dyavar Shetty

    (University of Nebraska Medical Center)

  • Adam Szlachetka

    (University of Nebraska Medical Center)

  • Morgan Johnston

    (University of Nebraska Medical Center)

  • Michellie Thurman

    (University of Nebraska Medical Center)

  • Daniel J. Munt

    (Creighton University)

  • Alekha K. Dash

    (Creighton University)

  • Milica Markovic

    (University of Nebraska Medical Center)

  • Arik Dahan

    (Ben-Gurion University of the Negev)

  • Yazen Alnouti

    (University of Nebraska Medical Center)

  • Alborz Yazdi

    (Exavir Therapeutics, Inc.)

  • Bhavesh D. Kevadiya

    (University of Nebraska Medical Center)

  • Siddappa N. Byrareddy

    (University of Nebraska Medical Center)

  • Samuel M. Cohen

    (University of Nebraska Medical Center)

  • Benson Edagwa

    (University of Nebraska Medical Center
    University of Nebraska Medical Center
    Exavir Therapeutics, Inc.)

  • Howard E. Gendelman

    (University of Nebraska Medical Center
    University of Nebraska Medical Center
    University of Nebraska Medical Center
    Exavir Therapeutics, Inc.)

Abstract

Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led to an 18-carbon chain modified ester prodrug nanocrystal (coined NM2DTG) with the potential to sustain yearly dosing. Here, we show that the physiochemical and pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injection. Significant plasma drug levels are recorded up to a year following injection. Tissue sites for prodrug hydrolysis are dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affect an extended NM2DTG apparent half-life recorded by PK parameters. The NM2DTG product can impact therapeutic adherence, tolerability, and access of a widely used integrase inhibitor in both resource limited and rich settings to reduce HIV-1 transmission and achieve optimal treatment outcomes.

Suggested Citation

  • Suyash Deodhar & Brady Sillman & Aditya N. Bade & Sean N. Avedissian & Anthony T. Podany & JoEllyn M. McMillan & Nagsen Gautam & Brandon Hanson & Bhagya L. Dyavar Shetty & Adam Szlachetka & Morgan Joh, 2022. "Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30902-7
    DOI: 10.1038/s41467-022-30902-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30902-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-30902-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Brady Sillman & Aditya N. Bade & Prasanta K. Dash & Biju Bhargavan & Ted Kocher & Saumi Mathews & Hang Su & Georgette D. Kanmogne & Larisa Y. Poluektova & Santhi Gorantla & JoEllyn McMillan & Nagsen G, 2018. "Creation of a long-acting nanoformulated dolutegravir," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Martina Kovarova & S. Rahima Benhabbour & Ivana Massud & Rae Ann Spagnuolo & Brianna Skinner & Caroline E. Baker & Craig Sykes & Katie R. Mollan & Angela D. M. Kashuba & J. Gerardo García-Lerma & Russ, 2018. "Ultra-long-acting removable drug delivery system for HIV treatment and prevention," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    3. Denise A. Cobb & Nathan Smith & Suyash Deodhar & Aditya N. Bade & Nagsen Gautam & Bhagya Laxmi Dyavar Shetty & JoEllyn McMillan & Yazen Alnouti & Samuel M. Cohen & Howard E. Gendelman & Benson Edagwa, 2021. "Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Isabella C. Young & Ivana Massud & Mackenzie L. Cottrell & Roopali Shrivastava & Panita Maturavongsadit & Alka Prasher & Andres Wong-Sam & Chuong Dinh & Tiancheng Edwards & Victoria Mrotz & James Mitc, 2023. "Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Manse Kim & Claire E. Johnson & Alan A. Schmalstig & Ayano Annis & Sarah E. Wessel & Brian Horn & Amanda Schauer & Agata A. Exner & Jason E. Stout & Angela Wahl & Miriam Braunstein & J. Victor Garcia , 2022. "A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30902-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.