Background
Currently, there are 20.2 million girls and women living with HIV and nearly half of pregnancies are unintended. This leads to a global economic and health burden for women and as such, technologies that can prevent HIV infections and unintended pregnancies are warranted. We evaluated a long-acting (LA), injectable in-situ forming implant (ISFI) as a multi-purpose prevention technology (MPT) to co-formulate cabotegravir (CAB) and medroxyprogesterone acetate (MPA) with the incorporation of a contrast agent for in vivo visualization and ease of retrievability. Here, we investigated time-to-completion (TTC) PK, long-term safety, implant visualization, and PK tail in BALB/c mice.
Methods
BALB/c mice were administered a single 50 µL injection subcutaneously (SC) of ISFIs containing CAB (500 mg/mL; 1251 mg/kg), MPA (36 mg/mL; 90 mg/kg) and 10% Barium sulfate (BaSO4). CAB and MPA plasma concentrations were measured until TTC. ISFIs were surgically removed at day 90 and 180 (n=6) to assess CAB and MPA PK tail. Subcutaneous tissue was harvested (n=5/timepoint) and the injection site was scored for local inflammation and plasma was collected to assess systemic inflammatory response. Implant visualization and migration was assessed by X-ray imaging.
Results
Overall, the MPT ISFI was well tolerated in mice. The median (range) plasma CAB and MPA concentrations during the first 6 months were 18750 (3940-34800) and 1.70 (1.44-1.86) ng/mL, respectively (Fig 1A). CAB levels maintained above the 4X PA-IC90 for 210 days with median (range) plasma levels at 17050 (870-30100) ng/mL (Fig 1A). In contrast MPA concentration was below limit of quantification by day 210 (< 0.5 ng/mL) (Fig 1A). Following removal of ISFIs at day 90 and 180, all animals elicited undetectable plasma CAB within 2-3 weeks. Plasma MPA was undetectable at day 1 following implant removal for all animals. X-ray imaging demonstrated the ability to visualize the implants for at least 180 days with no signs of implant migration (Fig 1B; showing n=2 animals).
Conclusions
We demonstrated long-term safety and PK of a first-in-line LA MPT ISFI releasing CAB and MPA. Our findings showed the ability to visualize the implants with no evidence of implant migration. CAB and MPA elicited undetectable plasma concentration after implant removal highlighting the potential for a discrete and reversible MPT option for adolescent girls and women.