An Ultra-Long-Acting Dimeric Bictegravir Prodrug Defined by a Short Pharmacokinetic Tail

TL;DR

Researchers developed a long-lasting HIV drug that can maintain effective levels in the body for months after a single injection.

Contribution

A novel dimeric prodrug of bictegravir is shown to sustain high drug levels for six months with a short pharmacokinetic tail.

Findings

The homodimeric prodrug NMXBIC maintains plasma BIC levels above PA-IC95 for six months after a single injection in rats.

NMXBIC and NM2BIC are well tolerated in rabbits after repeated injections.

NMXBIC's high drug loading and physicochemical properties contribute to its ultra-long-acting profile.

Abstract

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 in Sprague Dawley rats. 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.

Figures