Background: The present clinical trial investigated the potential influences of dosage and age on the pharmacokinetic properties and safety profile of HSK3486, and whether any adjustment in dosing regimen is necessary in elderly patients.Methods: Twenty-four elderly participants (65–73 years) were apportioned to three equal cohorts to receive a single IV bolus of 0.2, 0.3, and 0.4 mg/kg HSK3486, respectively. An additional control group comprised eight non-elderly participants (21–44 years), who each received a single IV bolus dose of 0.4 mg/kg. Safety was assessed throughout the study, and the clinical effects were assessed based on modified observer’s assessment of alertness/sedation and bispectral index (BIS) monitor. Pharmacokinetic parameters were calculated.Results: The rates of drug-related adverse reactions among the elderly groups were a little higher than that of the non-elderly, and were slightly higher in the elderly receiving 0.4 mg/kg compared with the elderly given lower doses. The pharmacokinetic characteristics of 0.4 mg/kg HSK3486 in the elderly and non-elderly were comparable. The time to recovery was similar in elderly 0.3 mg/kg, elderly 0.4 mg/kg and non-elderly 0.4 mg/kg groups. In the elderly 0.2 mg/kg group, the time to loss of consciousness was a little longer, and the time to recovery was shorter, relative to the other three groups.Conclusions: Administration of 0.3 mg/kg to the elderly and 0.4 mg/kg to the non-elderly were similarly efficacious. A dose of HSK3486 of 0.3 mg/kg may be chosen for clinical use in elderly patients.

Abstract Background GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator (class I) that can inhibit HBV replication by interfering with the assembly and disassembly of HBV nucleocapsid. Here, we evaluated its antiviral activity, pharmacokinetics (PK), and tolerability in a double-blind, randomized, parallel, entecavir-controlled study. Methods Twenty four chronic HBV patients were randomized to receive a 28-day course of GLS4 (120 or 240 mg) and ritonavir (100 mg) combination (cohorts A and B, respectively) or entecavir treatment (cohort C) at a 1:1:1 ratio. Patients were followed-up for 40 days in a phase 1b study. Results The GLS4/ritonavir combination was a tolerated combination for the treatment of chronic HBV infection. A total of two, three, and three subjects presented with alanine aminotransferase flare in cohorts A, B and C, respectively. This contributed to the withdrawal of one, two, and one patient from cohorts A, B and C, respectively. The mean Ctrough of GLS4 was 205–218 ng/mL, which was approximately 3.7–3.9 times the EC90 (55.8 ng/mL), with a lower accumulation (accumulation rate: 1.1–2.0). In cohorts A, B and C, the mean declines in HBV DNA after 28 days of treatment were -1.42, -2.13, and -3.5 log10 IU/mL; in hepatitis B surface antigen were -0.06, -0.14, and -0.33 log10 IU/mL; in pregenomic RNA were -0.75, -1.78, and -0.96 log10 copies/mL; and in hepatitis B core antigen (were -0.23, -0.5, and -0.44 log10 U/mL, respectively. Conclusions Treatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection.

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