A Randomized Phase 1 Study Evaluating Pharmacokinetics, Safety, and Tolerability of a High‐Concentration, Long‐Acting Cabotegravir Formulation in Adults Without HIV

Long-acting (LA) cabotegravir 200-mg/mL (CAB200) injections are approved for HIV-1 prevention and as a complete LA HIV-1 treatment regimen with rilpivirine. A high-concentration suspension formulation, cabotegravir 400 mg/mL (CAB400-D), was developed to enable less frequent dosing and self-administration. This phase 1, double-blind, randomized study (NCT04484337) evaluated intramuscular (IM) gluteal, subcutaneous (SC) abdominal, and IM thigh CAB400-D injections (200-800 mg [0.5-2.0 mL]) in adults without HIV, using CAB200 injections as active control. Co-administration with recombinant human hyaluronidase (rHuPH20), topical nonsteroidal anti-inflammatory drug, or topical steroid was evaluated for some SC injections. Pharmacokinetics, adverse events (AEs), and participant-reported outcomes were assessed. Overall, 138 participants were enrolled. Absorption was faster with CAB400-D versus CAB200. Within 4 weeks, CAB400-D plasma exposures were similar across administration routes and higher than those of CAB200. Co-administration with rHuPH20 increased the spontaneous absorption rate of CAB400-D but not CAB200. No deaths or drug-related serious AEs were observed. Five (4%) participants discontinued treatment due to AEs (injection-site reactions [ISRs], n = 3 discontinuations). Most (99%) participants experienced ≥ 1 ISR. Participants reported good acceptability of injections. Although CAB400-D injections demonstrated acceptable safety/tolerability, faster absorption than CAB200 limited potential dosing intervals to monthly dosing. Alternative cabotegravir formulations with longer dosing intervals are under clinical evaluation.