Single‐dose pharmacokinetics and safety of ACC017, a novel HIV integrase inhibitor, in healthy adult participants: A first‐in‐human study

32 Background: Since 2018, the World Health Organization has recommended integrase strand transfer inhibitors (INSTIs) as first-line and second-line antiretroviral therapies for all people living with human immunodeficiency virus (HIV). ACC017 is a novel INSTI with potent anti-HIV activity, an in vitro resistance profile different from those of other INSTIs and favourable preclinical safety and pharmacokinetic properties, which is being developed for the treatment of HIV-1 infection. Methods: This randomized, double-blind, placebo-controlled, single-dose escalation study was conducted from 24 January 2024 to 20 May 2024, at a single centre in China. Thirty-six healthy participants, aged 18 to 55 years, were randomly assigned in a 4:1 ratio to receive a single dose of ACC017 (5, 20, 40, 80 or 120 mg) or placebo. Safety, tolerability and pharmacokinetics were evaluated through blood sampling, vital sign monitoring, electrocardiograms (ECGs), laboratory testing and pharmacokinetic analysis performed at regular intervals. This trial is registered with ClinicalTrials.gov, number NCT06278389. Results: Among the participants receiving ACC017 (5 to 120 mg), six subjects (22%, 6/27) reported seven adverse events (AEs), while three subjects (33%, 3/9) in the placebo group experienced four AEs. There was no statistically significant difference in the incidence of AEs between the two groups. All observed AEs were mild (Grade 1) and resolved spontaneously without intervention. Pharmacokinetic analysis showed that the average maximum plasma concentration (Cmax) of ACC017 was 193.7, 926.0, 900.8, 1671.7 and 2055.5 ng/mL across dose levels. The corresponding average areas under the plasma concentration-time curve from time zero to infinity (AUC0-∞) values were 3191.7, 15252.4, 16918.9, 29286.7 and 31759.4 h*ng/mL. Both Cmax and AUC0-∞ exhibited less than dose-proportional increases were observed. The median time to peak concentration (Tmax) ranged between 2 and 4 h with mean terminal half-life of 10.5 to 13.1 h. Discussion: ACC017 demonstrated good tolerability and dose-dependent, nonlinear pharmacokinetics. The inhibitory quotient (IQ), defined as the ratio of the clinical trough concentration (C24h) to the protein-binding adjusted 90% effective concentration (pa-EC90), was 3.2 to 29.8 for ACC017 at doses of 5 to 80 mg. These findings suggest that a once-daily oral dosing regimen of ACC017 at low doses may achieve therapeutic concentrations, supporting its potential as a promising antiretroviral therapy for HIV-1 infection.