Background:
The advantages of long-acting (LA) antiretroviral therapy (ART) for regimen adherence and sustained viral suppression are unquestioned. However, the requirement for bi-monthly clinic visits, injection site reactions, large dosing volumes, and long pharmacokinetic (PK) tail pose notable challenges to widespread LA ART use. Consequently, there is an immediate need for ultra-LA (ULA) ART capable of synchronizing dosing intervals with established six-month clinic visits. We report the PK and biodistribution profiles of two lead bictegravir (BIC) prodrug formulations in two animal species, in pursuit of a ULA BIC prodrug formulation with a short PK tail.
Methods:
Dimeric (MXBIC) and monomeric (M2BIC) BIC prodrugs were synthesized by esterification reactions and converted into aqueous surfactant stabilized solid drug nanosuspensions by high-pressure homogenization. Formulation stability, particle size, homogeneity, and surface charge were assessed. PK profiles, biodistribution, and terminal phase PK tails were evaluated in Sprague Dawley (SD) rats and rhesus macaques (RM) after intramuscular (IM) injection dosing.
Results:
Dimeric BIC prodrug formulations (NMXBIC formulations 1 and 2) demonstrated plasma BIC levels above the protein-adjusted 95% inhibitory concentration (PA-IC95) for > 6 months in SD rats after a single 45 mg BIC.eq./kg IM injection. Increasing the formulation concentration of NMXBIC by 1.5 fold (NMXBIC formulation 2) and subsequent reduction of injection volume boosted plasma BIC levels, but doubling the dose for formulation 2 in SD rats did not lead to a proportional increase in plasma BIC levels. Specifically, BIC levels following NMXBIC formulation 2 dosing were sustained at levels ≥ 14x PA-IC95 for 6 months. In RM, a single IM injection of NMXBIC (100mg. BIC eq./kg) sustained plasma BIC levels at ≥ 4x PA-IC95 for more than 6 months. Notably, regardless of the dose and species, plasma BIC levels after NMXBIC treatment exhibited rapid drug decay after 7 months, demonstrating a short PK tail (Figure A-B). In contrast, the monomeric BIC prodrug formulation (NM2BIC) exhibited a much slower BIC plasma decay curve after 7 months post-dosing in RM. An equivalent booster dose of NM2BIC (50 mg. BIC eq./kg) in RM on day 217 resulted in higher plasma BIC levels than the corresponding time points after the first injection.
Conclusions:
The dimeric NMXBIC formulation exhibits high plasma BIC exposure and a shorter PK tail with the potential for dosing at 6-month intervals.
