Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir
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Nagsen Gautam, JoEllyn M. McMillan, Devendra Kumar, Aditya N. Bade, Qiaoyu Pan, Tanmay A. Kulkarni, Wenkuan Li, Nathan A Smith, Bhagya L. Dyavar Shetty, Brady Sillman, Adam Szlachetka, Benson J. Edagwa, Howard E. Gendelman, Yazen Alnouti
bioRxiv
January 19, 2021
To prevent the spread of HIV/AIDS globally, much research has been done with a focus on treating and preventing the occurrence of HIV-1. Currently, the most effective long-term treatment is a single cabotegravir (CAB) shot given every eight weeks. However, researchers are eager to find ways to improve upon existing CAB treatments to increase the drug half-life, decrease side effects, and improve its effectiveness in preventing viral transfer.
In general, CAB is unique in structure and antiretroviral properties. Specifically, CAB LA PK test results have shown it has extended half-life and is limited in drug-drug interactions (DDI) compared to other treatments, and it has a low aqueous solubility and high melting point that make it ideal for high-concentration parenteral formulation. Although this treatment is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate treatments in HIV-1 prevention, it’s limited by the large dosing requirements, which often cause reactions at the injection site and the need for continued health monitoring.
In this study, researchers created lipophilic fatty acid ester CAB prodrug nanoformulations with extended PK properties (called NMCAB and NM2CAB based on their carbon length). NM2CAB specifically showed an effective PK profile for up to one year along with exponential increases in terminal half-life and CAB mean residence time. These formulations provide new opportunities to explore in the long-term treatment of HIV and the long-term eradication of the virus.
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