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

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. This study was registered in the Chinese Drug Clinical Trials Registration and Information Publicity Platform (http://www.chinadrugtrials.org.cn; registration No. CTR20180587; first public release date: 2 May 2018), a registry recognized by the Chinese National Medical Products Administration (NMPA).