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

Li, Xiaojiao; Yang, De‐Ming; Li, Qianqian; Wang, Hong; Wang, Meng; Yan, Pangke; Wu, Nan; Li, Fangqiong; Ma, Shengming; Ding, Yanhua; Liu, Jingrui; Wang, Hushan

doi:10.3389/fphar.2021.735700

Cited by 34 publications

(61 citation statements)

References 22 publications

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“…Our data also suggest that ciprofol was associated with slightly less pronounced effects on the cardiovascular system, with its impacts on heart rate and blood pressure being non-inferior to those of propofol. Ciprofol was also significantly safer than propofol as indicated by the reduced incidence of intubation responses in this patient group, in line with prior preclinical work and findings from preliminary clinical efficacy studies [ 9 , 10 , 14 ].…”

Section: Discussionsupporting

confidence: 85%

“…In general, ciprofol is associated with similar adverse side effects to those observed following propofol treatment, primarily affecting the respiratory and cardiovascular systems. There is also some evidence to suggest that ciprofol may exhibit lower rates of injection site pain and adverse respiratory effects as compared to propofol given that it is prepared at a lower concentration in the aqueous phase of the emulsion [ 10 ]. However, as ciprofol was only recently developed, limited data are currently available regarding its use for the induction of general anesthesia.…”

Section: Introductionmentioning

confidence: 99%

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The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study

et al. 2022

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Background Ciprofol is a recently developed, short-acting γ-aminobutyric acid receptor agonist sedative that is more potent than propofol, but there have been few clinical studies of this agent to date. Here, we sought to examine the safety and efficacy of ciprofol use for the induction of general anesthesia in individuals undergoing gynecological surgery. Methods Women between the ages of 18 and 60 years (ASA physical status 1 or 2) who were scheduled to undergo elective gynecological surgery under general anesthesia were randomly assigned to two equally sized groups in which anesthesia induction was performed using either ciprofol or propofol. General anesthesia induction success rates were the primary outcome for this study, while secondary outcomes included changes in BIS during the 10 min following the first administration of the study drug, the duration of successful induction, and adverse event incidence. Results A total of 120 women were included in the study. A 100% rate of successful induction was achieved in both the ciprofol and propofol groups, with no significant differences between these groups with respect to the duration of successful induction (34.8 ± 15.5 s vs 35.4 ± 9.5 s, P = 0.832), the time to the disappearance of the eyelash reflex (33.7 ± 10.6 s vs 34.0 ± 6.5 s, P = 0.860), or tracheal intubation (58.2 ± 31.1 s vs 53.9 ± 25.4 s, P = 0.448). Adverse event rates, including intubation responses, were significantly lower in the ciprofol group as compared to the propofol group(20% vs 48.33%, P = 0.0019). Ciprofol was associated with reduced injection pain relative to propofol (16.7% vs 58.3%, P < 0.001). Conclusions Ciprofol exhibits comparable efficacy to that of propofol when used for the induction of general anesthesia in individuals undergoing gynecological surgery and is associated with fewer adverse events.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study

et al. 2022

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“…Plasma concentrations of HSK3486 and propofol were measured by validated liquid chromatography tandem mass spectrometry (LC-MS/MS) with a low limit of quantification (LLOQ) of 5 ng/mL. A plasma concentration below LLOQ was recorded as below the quantitation limit (BQL) [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…After initial evaluations of absorption, distribution, metabolism, and excretion (ADME) processes [ 19 ], the maximum concentration ( C max ), time to C max ( t max ), terminal elimination half-life ( t 1/2 ), and mean residence time (MRT) were similar between HSK3486 and propofol, while clearance (CL), apparent volume of distribution ( V d ) and apparent volume of distribution at steady state ( V ss ) were different in a phase 1 trial [ 20 ]. In addition, a study on age-related effects of HSK3486 revealed that a dose of 0.3 mg/kg was similarly efficacious in the elderly compared with 0.4 mg/kg in non-elderly patients [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of HSK3486 for Anesthesia/Sedation in Patients Undergoing Fiberoptic Bronchoscopy: A Multicenter, Double-Blind, Propofol-Controlled, Randomized, Phase 3 Study

Luo

Zhang

et al. 2022

CNS Drugs

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Background Fiberoptic bronchoscopy is a complex procedure with the need for sufficient patient anesthesia/sedation while maintaining safety. This trial aimed to evaluate the efficacy, safety, and pharmacokinetics of HSK3486 during fiberoptic bronchoscopy. Methods This multicenter, double-blind, randomized, non-inferiority, parallel-group phase 3 trial was conducted in patients who underwent fiberoptic bronchoscopy. Patients randomly received HSK3486 0.4 mg/kg (N = 134) or propofol 2.0 mg/kg (N = 133). The primary efficacy endpoint was the successful rate of fiberoptic bronchoscopy, and secondary efficacy endpoints included successful induction of anesthesia/sedation, duration, time to being fully alert, and time to patient discharge. Safety assessments and drug concentrations were also measured. Results A total of 267 patients completed fiberoptic bronchoscopy, with a success rate of 100% and a 95% confidence interval of − 2.8 to 2.8% for the difference between the groups, which met the predesigned criteria of > − 8%, confirming the noninferiority of anesthesia/sedation produced by HSK3486 compared to propofol. Among the secondary efficacy endpoints, only time to full alertness (median 8.50 vs. 6.00 min, P = 0.012) and time to discharge (median 13.00 vs. 9.87 min, P = 0.002) were slightly longer in the HSK3486 group. The incidence of adverse events was significant lower in the HSK3486 group (52.6 vs. 76.5%, P < 0.001) mainly because of less pain on injection (4.4 vs. 39.4%, P < 0.001) compared to the propofol group. HSK3486 had a similar terminal elimination half-life as propofol. Conclusions HSK3486 exhibited non-inferiority anesthesia/sedation compared to propofol in patients undergoing fiberoptic bronchoscopy, and had a good safety profile with a lower incidence of pain on injection. Trial Registration Clinicaltrials.gov, NCT04111159, registered on

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“…HSK3486 is a candidate intravenous drug that was developed for anaesthesia induction and maintenance ( Figure 1 ) [ 1–3 ]. HSK3486 has been investigated in several Phase I to III clinical trials that enrolled approximately 500 subjects, including healthy subjects, intensive care unit patients and those undergoing fibreoptic bronchoscopy, colonoscopy, gastroscopy, or elective surgery [ 2 , 4–6 ]. Results showed that the clinical characteristics of HSK3486 were comparable to propofol; the potency of HSK3486 was equivalent to propofol at 1/4 − 1/5 of the dosage; the plasma-level time curve for HSK3486 resembled that of propofol, and may be divided into three phases, an initial distribution phase (t 1/2α =2.0 min), a subsequent redistribution phase (t 1/2β =34.9 min) and a terminal elimination phase (t 1/2γ =6.2 h) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment

Yue

Liu

et al. 2022

Annals of Medicine

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Background The primary objective of this study was to investigate if hepatic impairment alters the safety, pharma c okinetics, and pharmacodynamics of HSK3486. Research design and methods This was a clinical trial of HSK3486 in subjects with normal hepatic function ( n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. Results In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). Conclusions Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. Trial registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596). Key Message HSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects. There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

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

Cited by 34 publications

References 22 publications

The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study

The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study

Efficacy and Safety of HSK3486 for Anesthesia/Sedation in Patients Undergoing Fiberoptic Bronchoscopy: A Multicenter, Double-Blind, Propofol-Controlled, Randomized, Phase 3 Study

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment

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