Abstract Body

Significant interest in long-acting parenteral (LAP) antiretroviral drugs (ARVs) has set the bar for future HIV/AIDS care. LAP ARVs can improve treatment adherence and positively affect drug resistance and systemic toxicity patterns. Cabotegravir (CAB), a potent HIV integrase inhibitor, now in phase II clinical trials as a LAP (CAB-LAP), currently demonstrates sustained plasma drug levels in humans up to 52 days after single intramuscular dose. We proposed that CAB-LAP could be modified to further reduce injection volumes and improve pharmacokinetic (PK) profiles. To this end, a nanoformulated prodrug of CAB (called NMCAB) was made to extend the drug half-life and antiretroviral activities and enabled the creation of a long-acting dolutegravir (DTG).

CAB was chemically conjugated to myristoyl chloride, increasing its hydrophobicity. NMCAB was produced by high-pressure homogenization with poloxamer 407. Uptake and retention were tested in human monocyte-derived macrophages (MDM). Antiretroviral activity was evaluated by HIV reverse transcriptase (RT) activity and HIV-1p24 expression. Pharmacokinetics of NMCAB was evaluated in Balb/C mice and compared to parent drug formulations after a single intramuscular injection of 15 or 45 mg/kg. The plasma drug levels were monitored for two months.

NMCAB was efficiently taken up by MDM with sustained slow release of up to 30 days. Notably, the parent drug formulations were eliminated after a single day of treatment. Drug crystals were observed by transmission electron microscopy in NMCAB treated MDM, but not in cells treated with parent drug. NMCAB showed sustained antiretroviral activity in MDM as determined by both RT activity and HIV-1p24 staining for up to 30 days after drug removal. In contrast, parent drug formulations failed to inhibit viral growth one day after drug loading. In in vivo studies, NMCAB showed reduced burst release but was cleared more slowly, resulting in drug levels at later time points being up to 100 times higher than the parent drug formulations (Figure). Replicate results were seen for a created DTG prodrug and will be discussed.

Both CAB and DTG prodrugs were successfully synthesized and encapsulated into nanoparticles with clear improvements as a LAP formulation for antiretroviral therapy.