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<p>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&#xa0;mg administered over 30&#xa0;min), an open-label infusion-duration cohort evaluating 0.75&#xa0;mg administered over 15, 5, or 2&#xa0;min, and a CYP2D6 poor metabolizer cohort receiving a single 1.5&#xa0;mg dose over 30&#xa0;min. A total of 56 participants were enrolled. The maximum tolerated dose (MTD) of SHR8554 was 3&#xa0;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&#xa0;mg dose range, with a mean elimination half-life of approximately 6&#xa0;h. Infusion duration had minimal impact on overall drug exposure. A measurable analgesic effect was first observed at 1.5&#xa0;mg, with onset within 10&#xa0;min after administration and duration of approximately 4&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月20日

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  • Lifang Zhang,
  • Ge Luo,
  • Haiying Wang,
  • Honggang Lou,
  • Min Yan

摘要

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.