180: Comparative Structure, In Vitro Efficacy & Pharmacokinetics of HSK3486 & Propofol

Statement of Purpose: HSK3486 is a novel intravenous anesthetic induction agent that is based on the structural modification of propofol with a comparable safety profile and significantly less injection-site pain. Propofol is a phenol (2,6-diisopropylphenol) with a substitution of hydrogen by a hydroxy group at the 2 position. HSK3486 ((R)-2-(1-cyclopropylethyl)-6-isopropylphenol) preserves the main structure of propofol and substitutes a 6-methyl group with a cyclopropyl ring to optimize target selection, reduce adverse events, enhance potency, increase metabolic stability and increase permeability in the brain. A previous study demonstrated that compared with propofol, HSK3486 had greater lipophilicity, a lower unbound drug concentration in the aqueous phase and decreased injection-site pain; these benefits were related to HSK3486’s novel chemical structure.1 The purpose of the present studies was to describe and compare the structure, in vitro efficacy and pharmacokinetics (PK) of HSK3486 and propofol.

Description of Methods & Materials: An in vitro efficacy comparison of HSK34862 and propofol3 using the [35S]TBPS binding assay of γ-aminobutyric acid type A (GABAA)-gated chloride channels and automated whole-cell patch-clamp experiments were conducted to assess the affinity and mediation of GABAA currents. To assess PK parameters, a single intravenous bolus of HSK3486 (dose range, 0.128--0.810 mg/kg) was administered to healthy adult Australian participants. The time required to reach maximum concentration (T_max), peak concentration (C_max), area under the curve (AUC), clearance (CL), volume of distribution in steady state (V_ss), and apparent volume of distribution (V_d) were measured.

Data & Results: In vitro comparison of HSK3486 and propofol using the [35S]TBPS binding assay of GABAA-gated chloride channels and automated whole-cell patch-clamp experiments showed that HSK3486 was more active on the target GABAA in both the binding and functional assays. HSK3486 required only one-fifth of the concentration of propofol to achieve equivalent activity (IC₅₀: HSK3486, 2.1 uM; propofol, 10.8 uM; EC₅₀: HSK3486, 1.1 uM; propofol, 5.3 uM). In the PK study, the T_max of HSK3486 was rapidly achieved at 1 minute after dosing. HSK3486 demonstrated a linear PK profile, as the exposure level increased proportionally to dose. The plasma concentration of HSK3486 was characterized by 3-phase elimination. The C_max and AUC of HSK3486 showed proportional increases with increasing dose, while CL, V_ss, and V_d showed no dose dependence. HSK3486 was rapidly eliminated after a single injection.

Interpretation, Conclusion or Significance: HSK3486 and propofol are phenol derivatives and non-barbiturates and have the same mechanism of action functioning as direct agonists of the GABAA receptor. Overall, the PK profile of HSK3486 is similar to the reported PK characteristics of propofol. HSK3486 differs from propofol in the inclusion of a cyclopropyl group and this novel structure decreases the amount of lipid required for emulsification and increases potency and lipid solubility. HSK3486 has been shown to reduce the incidence of injection-site pain in clinical studies,4,5 further supporting its continued development. References 1. Anaesthesist. 2001;50(11):842-845. 2. Haisco. Data on file. 3. Br J Anaesth. 2003;90(2):199-211. 4. Basic Clin Pharmacol Toxicol. 2022;131(2):138-148. CNS Drugs. 2022;36(3):301-313.

Disclosures: WLD, MH, PY, RZ and XL are employees and shareholders of Haisco.