Distribution of long-acting (LA) cabotegravir (CAB) in plasma, mucosal tissues, and associated fluids after a single ultrasound-guided intramuscular (IM) injection in healthy adult participants


BACKGROUND: CAB LA dosed at 2-month intervals demonstrated virologic efficacy in maintaining HIV-1 suppression as part of a dual regimen with rilpivirine LA and is undergoing Phase 3 evaluation as a single agent for HIV-1 pre-exposure prophylaxis (PrEP). CAB pharmacokinetics (PK) in plasma and mucosal tissues associated with sexual HIV-1 transmission were evaluated following single CAB LA IM injection.
METHODS: Participants received 4 weeks of daily oral CAB 30mg, followed by 14-42 day washout and a single ultrasound-guided gluteal IM injection of CAB LA 600mg (3mL). PK samples were collected after oral dosing and through 12 weeks post-injection in plasma, rectal tissue (RT), cervical tissue (CT), vaginal tissue (VT), cervicovaginal fluid (CF), and rectal fluid (RF). CAB concentrations were determined by HPLC-MS/MS. PK parameters were estimated using noncompartmental analysis. Pearson correlations of time-matched tissue and plasma concentration pairs were determined.
RESULTS: Nineteen participants (10F, 9M) enrolled with mean age 33 years, weight 79.4 kg, and BMI 27.2 kg/m2. Two participants withdrew before injections, one did not undergo tissue sampling, and one was hospitalized for unrelated serotonin syndrome. Median CAB concentration-time profiles are presented by matrix (Figure). Median CAB tissue:plasma ratio was 9-10% in RT (r=0.96), 14-18% in CT (r=0.94), 14-16% in VT (r=0.92), 8-13% in CF (r=0.65), 32-45% in RF (r=0.19). Geometric mean (CVb%) plasma half-life was 19.1 (81.4%) days.
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CONCLUSIONS: Plasma CAB PK was consistent with prior studies, and CAB concentrations in tissue and fluid were proportional to plasma over time. Correlations with plasma concentrations were stronger for tissue (RT, CT, VT) than for luminal fluid (CF and RF). Tissue concentrations were 1/6th (CT, VT) to 1/10th (RT) of plasma concentrations. With sufficient distribution into mucosal tissues associated with sexual HIV-1 transmission, CAB tissue:plasma ratios may serve as important measurements in evaluating CAB LA as an effective PrEP agent.