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

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 Johnston, Michellie Thurman, Daniel J. Munt, Alekha K. Dash, Milica Markovic, Arik Dahan, Yazen Alnouti, Alborz Yazdi, Bhavesh D. Kevadiya, Siddappa N. Byrareddy, Samuel M. Cohen, Benson Edagwa () and Howard E. Gendelman ()
Additional contact information
Suyash Deodhar: University of Nebraska Medical Center
Brady Sillman: 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
Howard E. Gendelman: University of Nebraska Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30902-7

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