Nature communications · 2026
An ultra-long-acting dimeric bictegravir prodrug defined by a short pharmacokinetic tail.
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Nayan Mohammad Ullah, Sillman Brady, Das Srijanee, Hanson Brandon W, Sultana Ashrafi, Le Nam Thai Hoang, Deodhar Suyash, Gowda Bhoomika, Dash Prasanta K, Agrawal Satish, Dash Alekha K, Cohen Samuel M, Zhang Chen, Gendelman Howard E, Edagwa Benson
Аннотация
Ultra-long-acting (ULA) antiretroviral parenteral formulations, with low injection volumes, high resistance barriers, and short pharmacokinetic (PK) tails, can transform HIV-1 therapeutics. Here, we converted bictegravir (BIC), a potent daily oral antiretroviral drug, into monomeric and homodimeric ester prodrugs. The homodimeric prodrug nanosuspension, NMXBIC, shows sustained plasma BIC levels > 16 times the protein-adjusted 95% inhibitory concentration (PA-IC95) for six months after a single injection in Sprague Dawley rats. The results paralleled a short PK tail with the potential for late dose forgiveness. The monomeric prodrug nanosuspension, NM2BIC, shows lower year-long plasma BIC concentrations above PA-IC95 after a single injection. After repeated injections, NMXBIC and NM2BIC are well tolerated in New Zealand White rabbits. NMXBIC's physicochemical properties and high BIC loading/unit mass of the prodrug contribute to its unique ULA PK profile. These results support its development as a ULA formulation for HIV-1 treatment and prevention.