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

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Abstract
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.

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