Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects

Abstract

Aims This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. Methods A single dose of 0.4 mg/kg [14C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. Results The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0‐t) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half‐life (t1/2) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5–14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. Conclusion HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.

Safety, Pharmacokinetics, and Pharmacodynamics of a Single Bolus of the γ-aminobutyric Acid (GABA) Receptor Potentiator HSK3486 in Healthy Chinese Elderly and Non-elderly

“…The plasma exposure of HSK3486 among the elderly groups (0.2, 0.3, and 0.4 mg/kg) increased gradually with the increase in dose, with no significant differences in distribution and elimination of HSK3486. This is consistent with a previous clinical pharmacokinetic study of HSK3486 with healthy adult subjects (Bian et al, 2020). After a single intravenous dose of 0.4 mg/kg HSK3486 in healthy adult subjects, the AUC, T max , t 1/2 , apparent volume of distribution during the terminal phase (Vz) and clearance were 289.2 h*ng/ ml, 0.0333 h, 1.5 h, 3.0 L/kg, and 1.4 L/h/kg, respectively, which appeared comparable to corresponding parameters from our study.…”

“…In this study, there were no spontaneous reports of pain on injection with HSK3486, which is consistent with a previous study (Bian et al, 2020). Because the most common adverse reaction associated with propofol is pain on injection, with an incidence of 25-74% in adult patients (Abad-Santos et al, 2003), the absence of pain on injection with HSK3486 is considered an improvement.…”

“…Results indicate that the effective characteristics of HSK3486 are consistent with that of propofol, but the former can achieve the same anesthesia depth with 20-25% the dosage, and is associated with less inhibition of cardiac function and more stable hemodynamics. The plasma concentration of HSK3486 undergoes 3-phase elimination, with half-lives of initial, second, and terminal elimination phases of 2.0, 34.9, and 6.2 h, respectively, that are comparable with propofol (Bian et al, 2020;Ludbrook et al, 2021) (NCT04054063, NCT04037657, NCT04033939, NCT03773835, NCT03698617, NCT03709056, NCT03773042, NCT03808844, NCT03674008).…”

“…HSK3486, a gamma-aminobutyric acid (GABA) receptor potentiator similar to propofol, is a new candidate drug for the intravenous induction and maintenance of anesthesia in clinical practice (Figure 1). Compared with propofol, HSK3486 causes significantly less injection pain and hypotension (Qin et al, 2017;Wei et al, 2017;Bian et al, 2020). Several clinical trials (phase I to III) concerning HSK3486 have been completed in China and Australia, with overall more than 500 subjects enrolled, including those healthy or undergoing colonoscopy, gastroscopy, or elective surgery.…”

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review

“…Ciprofol (HSK3486) is a propofol analogue formulated in an oilin-water emulsion. Its general characteristics are similar to those of propofol 147 with a decreased frequency of pain on injection, 148 possibly because of reduced concentrations of free drug in plasma. Ciprofol is currently undergoing late-stage clinical trials for procedural sedation, 149 and trial registries indicate studies in general anaesthesia; however, none are yet reported.…”