Safety, tolerability, pharmacokinetics, and pharmacodynamics of SHR8554, a biased µ-opioid receptor agonist: a phase I trial in healthy volunteers.

Abstract

This randomized, placebo-controlled, dose-escalation phase I trial evaluated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of SHR8554, a biased µ-opioid receptor agonist, in healthy male volunteers under different infusion durations. The study included three cohorts: a randomized, double-blind, placebo-controlled single-infusion cohort (0.25-3 mg administered over 30 min), an open-label infusion-duration cohort evaluating 0.75 mg administered over 15, 5, or 2 min, and a CYP2D6 poor metabolizer cohort receiving a single 1.5 mg dose over 30 min. A total of 56 participants were enrolled. The maximum tolerated dose (MTD) of SHR8554 was 3 mg. The most common treatment-emergent adverse events (TEAEs) were dizziness, nausea, and vomiting, with higher incidence at increased doses and shorter infusion durations. PK analyses showed that systemic exposure (Cmax and AUC) increased in a slightly less than dose-proportional manner across the 0.75-3 mg dose range, with a mean elimination half-life of approximately 6 h. Infusion duration had minimal impact on overall drug exposure. A measurable analgesic effect was first observed at 1.5 mg, with onset within 10 min after administration and duration of approximately 4 h. SHR8554 increased pain tolerance and reduced numerical rating scale (NRS) scores in an exploratory cold pain model, although no clear dose-dependent trend was observed. SHR8554 was generally well tolerated within the tested dose range and demonstrated preliminary analgesic activity in healthy volunteers.