Assessments of Onset and Duration of Drug Effects and Pharmacokinetics by Dose Level of HSK3486, a New Sedative-Hypnotic Agent, in Healthy Female/Male Subjects: A Phase I Multiarm Randomized Controlled Clinical Trial.

BACKGROUND: Onset and duration of effects and pharmacokinetics of the novel anesthesia medication HSK3486 were examined after a single intravenous injection to evaluate its usefulness as a potential alternative to propofol.

METHODS: Phase Ia (male-only, blinded) and Ib (female-only, open-label) trials were both prospective randomized, dose escalation trials of a single intravenous injection of HSK3486 or either placebo or propofol. The primary aim of this first-in-human trial was safety through measurements of dose-related effects on cardiorespiratory functions, the central nervous system, laboratory parameters, and reported adverse events. The secondary aims were to determine initial pharmacokinetic parameters and to establish a dose regimen for sedation and general anesthesia for subsequent later-phase clinical trials.

RESULTS: A total of 50 healthy male subjects were enrolled in the phase Ia trial and 30 healthy female subjects in the phase Ib trial. No significant difference was found in the overall pattern of anesthetic effects between HSK3486 and propofol (all P > .05), but the sample size was not sufficiently large to make a confident assessment. Rapid onset and offset of dose-dependent sedation or general anesthesia after HSK3486 administration was found in male and female subjects with median central nervous system equilibrium half-life times of 1.3 and 1.8 minutes across cohorts in phases Ia and Ib and accompanied by mild hypotension and respiratory depression. Pharmacokinetics profiles revealed that there was no evidence that the groups were different (all P > .05), with a high clearance and distribution volume. In the phase Ia trial, the median terminal half-life (t1/2) for HSK3486 doses of 128, 192, 288, 432, 540, 648, and 810 μg/kg were 68.8, 64.7, 207.0, 210.7, 313.5, 293.5, and 245.7 minutes, respectively. In the phase Ib trial, the median t1/2 for HSK3486 doses of 288, 432, 540, 648, and 810 μg/kg were 68.5, 159.7, 122.7, 281.5, and 245.3 minutes, respectively. Treatment emergent adverse events (TEAEs) were reported in 50% and 53% of subjects in the phase Ia and Ib trials but were mostly related to minor events (eg, arterial catheter irritation). HSK3486 was well tolerated at dose levels up to 810 μg/kg in all subjects compared with propofol (odds ratio in phases Ia and Ib: 0.71 and 6.00; 95% confidence interval [CI], 0.09-4.85 and 0.47-314.71, respectively; all P > .05) and placebo (odds ratio in phase Ia: 0.95; 95% CI, 0.01-78.45; P > .05).

CONCLUSIONS: HSK3486 has potential clinical application for intravenous administration for the induction and maintenance of sedation and general anesthesia.