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

Yue Hu, Xiaojiao Li, Jingrui Liu, Hong Chen, Wenbo Zheng, Hong Zhang, Min Wu, Cuiyun Li, Xiaoxue Zhu, Jinfeng Lou, Pangke Yan, Nan Wu, Xiao Liu, Shiping Ma, Xu Wang, Yanhua Ding, Chengluan Xuan, Yue Hu, Xiaojiao Li, Jingrui Liu, Hong Chen, Wenbo Zheng, Hong Zhang, Min Wu, Cuiyun Li, Xiaoxue Zhu, Jinfeng Lou, Pangke Yan, Nan Wu, Xiao Liu, Shiping Ma, Xu Wang, Yanhua Ding, Chengluan Xuan

Abstract

Background: The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, 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 MessageHSK3486 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.

Keywords: Efficacy; HSK3486; hepatic impairment; pharmacokinetics; safety.

Conflict of interest statement

No potential conflict of interest was reported by the author(s). Pangke Yan, Nan Wu, Xiao Liu, Shiping Ma, Xu Wang are the employees of Haisco Pharmaceutical Group.

Figures

Figure 1.
Figure 1.
Chemical structure of HSK3486 and propofol (A), study design and flow chart (B and C).
Figure 2.
Figure 2.
Vital signs: (A) respiration rate; (B) mean arterial pressure; (C) systolic blood pressure; (D) diastolic blood pressure; (E) heart rate; (F) oxygen saturation (SpO2). Data are presented as mean＋standard deviation.
Figure 3.
Figure 3.
Plasma concentration-time curves for HSK3486 and its metabolite M4 in linear (A, C) and semi-log scale (B, D). Data are presented as mean＋standard deviation.
Figure 4.
Figure 4.
Mean MOAA/S score-time curves (A) and BIS curves (B) for subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment. Data are presented as mean＋standard deviation.
Figure 5.
Figure 5.
Scatterplots showing the correlations between HSK3486 exposure (AUC0-t) and time until fully alert (A); BISAUC0-t (B); BISpeak (C); and TBISpeak (D) in subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment.
Figure 6.
Figure 6.
Scatterplots showing the correlations between HSK3486 plasma concentration and MOAA/S scores (A), and mean HSK3486 plasma concentrations and mean BIS change from baseline (B) in subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment.

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