Background:
Antiretroviral therapy (ART) halts viral replication leading to reduced morbidity, mortality, and transmission of infection in people living with or at risk for HIV infection. However, therapeutic limitations remain. These include suboptimal adherence, adverse events, regimen tolerability, and viral resistance. To these ends, the need for ultra-long-acting (ULA) antiretroviral (ARV) formulations with extended duration of action cannot be overstated. Herein, we report the transformation of bictegravir (BIC) into prodrug formulations with apparent half-life extensions. The BIC prodrugs and corresponding nanocrystals were tested for their physicochemical and pharmacokinetic (PK) properties. The overarching goal was to create ULA BIC prodrug formulations with limited injection volumes and a shorter terminal phase PK tail.
Methods:
Dimeric (DiBIC) and monomeric (MBIC, M2BIC, M3BIC) BIC prodrugs were synthesized by one-step dimerization and mono-esterification reactions. The synthesized prodrugs were nanoformulated by high-pressure homogenization. The formed aqueous solid drug nanocrystals were stabilized by non-ionic surfactants. Prodrug stability, particle size, homogeneity, and surface charge were assessed. Cellular uptake and retention, antiretroviral efficacy, and cytotoxicity were tested in primary human monocyte-derived macrophages (MDM). Following a single intramuscular (IM) injection, PK and biodistribution (BD) profiles were evaluated in Balb/cJ mice, SD rats, and rhesus macaques.
Results:
The lead nanoformulated DiBIC (NDiBIC) and M2BIC (NM2BIC) were stable for at least six months and demonstrated drug loadings and encapsulation efficiencies of >75%, 230-450 nm size, and PDIs of 0.2-0.3. A single treatment of MDM with 25 µM of either NDiBIC or NM2BIC led to sustained intracellular drug l that led to protection against HIV-1ADA for up to 30 days. Importantly, PK testing of NDiBIC after a single IM injection of rodents at 45 mg BIC eq./kg dose produced plasma BIC concentrations at or above the protein-adjusted (PA) 95% inhibitory concentration (PA-IC95) for >7 months. The profiles demonstrated a shorter terminal phase PK tail. NM2BIC demonstrated plasma BIC concentrations at or above the PA-IC95for >11 months in rodents. Ongoing evaluation of NM2BIC in rhesus macaques demonstrates BIC plasma levels remain above the PA-IC95 at three months (Figure 1)
Conclusions:
The lead NDiBIC and NM2BIC prodrug formulations demonstrate the potential for beyond every six-month dosing interval of BIC.
PK testing of a single dose of BIC prodrug formulations (NMBIC, NM2BIC, NM3BIC or NDiBIC)