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<p>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 &gt; 16 times the protein-adjusted 95% inhibitory concentration (PA-IC<sub>95</sub>) 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-IC<sub>95</sub> 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.</p>

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An ultra-long-acting dimeric bictegravir prodrug defined by a short pharmacokinetic tail

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Mohammad Ullah Nayan,
  • Brady Sillman,
  • Srijanee Das,
  • Brandon W. Hanson,
  • Ashrafi Sultana,
  • Nam Thai Hoang Le,
  • Suyash Deodhar,
  • Bhoomika Gowda,
  • Prasanta K. Dash,
  • Satish Agrawal,
  • Alekha K. Dash,
  • Samuel M. Cohen,
  • Chen Zhang,
  • Howard E. Gendelman,
  • Benson Edagwa

摘要

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.