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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
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    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
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