Year: 2022
Type: article
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.
Source: Nature Communications
Authors: 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, Howard E. Gendelman
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: Combined Molecular Excision Therapy (CMET) for Eliminating HIV-1, G1398244641, Center for Humanized Mice, NanoART Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence, Limiting HIV establishment and maintenace by preserving intestinal immunity, G3186359280, Chronic HIV Infection and Aging in NeuroAIDS (CHAIN) Center, Nanomedicine and NeuroAIDS, G5041077875, Novel Adjunctive Therapies for NeuroAIDS, Molecular Mechanisms of HIV-1 Associated Encephalopathy, G6320211117, Neuroprotective Immunity and HIV Dementia, G9000262396, G9000346257, G9000352132, LASER ART for PreP, Neuroimmunology of Disease Training Program, Prodrug Formulations Create Sustained-Release Antiretrovirals, HIV-1DetectionandEliminationFrom CNS Mononuclear Phagocytes, Targeted lipid nanoparticles for gene therapeutics delivery approach to eradicating HIV reservoirs
OpenAlex ID: W4281706677