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

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 sho...

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Detalles Bibliográficos
Autores principales: Deodhar, Suyash, Sillman, Brady, Bade, Aditya N., Avedissian, Sean N., Podany, Anthony T., McMillan, JoEllyn M., Gautam, Nagsen, Hanson, Brandon, Dyavar Shetty, Bhagya L., Szlachetka, Adam, Johnston, Morgan, Thurman, Michellie, Munt, Daniel J., Dash, Alekha K., Markovic, Milica, Dahan, Arik, Alnouti, Yazen, Yazdi, Alborz, Kevadiya, Bhavesh D., Byrareddy, Siddappa N., Cohen, Samuel M., Edagwa, Benson, Gendelman, Howard E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184486/
https://www.ncbi.nlm.nih.gov/pubmed/35680875
http://dx.doi.org/10.1038/s41467-022-30902-7
Descripción
Sumario: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.