Multicompartmental pharmacokinetic assessment of long-acting cabotegravir for HIV preexposure prophylaxis in healthy persons - Abstract
Objectives: In clinical development as a Long-Acting (LA) injectable HIV preexposure prophylaxis, bototregravir is an integrase strand transfer inhibitor. Techniques: In healthy people, this phase I trial evaluated the pharmacokinetics of cabotegravir following repeated oral and single intramuscular (IM) LA doses in plasma and anatomical areas associated with sexual HIV-1 transmission. Participants received a single gluteal IM cabotegravir LA 600 mg injection guided by ultrasonography after a 28-day oral lead-in period of 30 mg of cabotegravir and a 14–42 day washout period. The aim of the study was to determine the levels of cabotegravir in plasma, cervical, vaginal, and rectal tissues, as well as in cervicovaginal and rectal fluids and up to Week 12 following intramuscular injection. Outcomes: Out of the nineteen enrolled subjects, sixteen finished the study by Week 52. Plasma contained cabotegravir, which was found in all fluids and tissues. Through week 12, the 90% maximum inhibitory concentration of cabotegravir in vitro was not met by the median plasma concentration. The rectal fluid had a median tissue-to-plasma cabotegravir concentration ratio of 0.32 during all visits, while the other tissues and fluids had a median ratio of 0.08-0.16. The adjusted R2 values were 0.78, 0.79, and 0.90 for the cabotegravir concentrations in plasma and the cervical, vaginal, and rectal tissues, respectively. Eighty-eight percent of subjects experienced injection-site responses, the majority of which were grade 1 (82%). Eleven major adverse events unrelated to drug use were reported by two subjects. In summary over time, the amounts of cabotegravir in tissues and fluids were proportionate to plasma, and there were significant connections between the concentrations in tissues and plasma. The tissue-to-plasma ratios of capegravir LA may be significant in comprehending its application as preexposure prophylaxis.