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

• DOI: 10.1038/s41467-022-30902-7
• Publication Date: 2022-06-09T10:03:35Z
• Authors: Suyash Deodhar; Brady Sillman; Aditya N. Bade; Sean N. Avedissian; Anthony T. Podany; JoEllyn M. McMillan; Nagsen Gautam; Brandon Hanson; Bhagya L. Dyavar ...; 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. Byrar...; Samuel M. Cohen; Benson Edagwa; Howard E. Gendelman
• Keywords: Dolutegravir; Atazanavir; Tolerability; Integrase inhibitor

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 nanocrystal (coined NM2DTG) with the potential sustain yearly dosing. Here, we show that physiochemical pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at muscle injection site adjacent lymphoid tissues following single parenteral injection. Significant plasma levels are recorded up year Tissue sites for hydrolysis dependent on dissolution release, drug-depot volume, perfusion, cell-tissue pH. Each affect extended NM2DTG apparent half-life PK parameters. The product can impact therapeutic adherence, tolerability, access widely used inhibitor in both resource limited rich settings reduce HIV-1 transmission achieve optimal treatment outcomes.