Organic chemistry

Adverse effect

Integrase inhibitor

Dolutegravir

Prodrug

Pharmacokinetics

Integrase

Viral load

Virology

Chemistry

Tolerability

Atazanavir

Drug delivery

Antiretroviral therapy

Drug

Human immunodeficiency virus (HIV)

Medicine

Pharmacology

Nature Communications

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.

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