NH6-00001

NH600001 is a new general anaesthetic drug with a structure similar to etomidate. The objective of this study was to investigate the relationship between concentrations of NH600001 and sedation efficacy based on data from phase I-II studies and factors influencing the pharmacokinetics and pharmacodynamics of NH600001. The dataset consisted of 2 phase I studies in healthy subjects and 1 phase II study in patients undergoing gastroscopy. Nonlinear mixed effects modeling was used in developing the population pharmacokinetics and pharmacodynamics (PopPK/PD) model of NH600001. Three-compartment model was used to describe the PK profile of NH600001. Parameters were used for allometric scaling on body weight, where the exponents were set to 0.75 for clearance and 1 for volumes. Co-administration of alfentanil hydrochloride influenced the distribution volume of the central compartment and clearance. Effect of patients undergoing gastroscopy (compared with healthy subjects) on clearance, the distribution volume of the superficial peripheral compartment and inter-compartmental clearance for deep peripheral compartment and central compartment was included the final PopPK model. The effect compartment model well characterized the PK/PD relationship of NH600001. Simulation results showed that an initial dose of 0.25 mg/kg of NH600001 resulted in rapid sedation, and three additional doses at 5-min intervals could maintain sedation for more than 20 min. A PopPK/PD model was successfully constructed for NH600001 in healthy subjects and in patients undergoing gastroscopy that could inform the dosing regimens of the forthcoming phase III study.

To evaluate the efficacy and safety of NH600001, a novel etomidate derivative, in gastrointestinal endoscopy, as well as its impact on adrenocortical function, two multicenter, double-blind, randomized, controlled clinical trials(NH600001-21 [Phase II trial] and NH600001-31 [Phase III trial]) were conducted in China. In NH600001-21, 160 gastroscopy subjects were randomized 1:1:1:1 to receive NH600001 (0.20, 0.25, or 0.30 mg/kg) and etomidate (0.30 mg/kg). In NH600001-31, 344 gastroscopy or colonoscopy subjects were randomized in a 1:1 ratio to receive NH600001 (0.25 mg/kg) and etomidate (0.30 mg/kg). The primary efficacy outcome was the rate of endoscopic success. Additionally, Safety and effects on adrenocortical function were also assessed. In NH600001-21, the 0.25 mg/kg NH600001 showed non-inferiority to etomidate based on the prespecified non-inferiority margin of -8% (Rate Difference [95% confidence interval], 5.0[-4.49 to 14.49]), whereas the 0.20 mg/kg and 0.30 mg/kg NH600001 did not meet statistical non-inferiority criteria (0[-11.54 to 11.54]; 0[-11.54 to 11.54]). The area under curve (AUC) of plasma cortisol change values within 0-4 h (∆Cortisol AUC_0-4h) were significantly higher in the NH600001 treatment groups than in the etomidate group (P < 0.01). In NH600001-31, NH600001 (0.25 mg/kg) showed non-inferiority to etomidate (1.16[-0.44 to 2.76]). ∆Cortisol AUC_0-4h in the NH600001 group, versus the etomidate group, were significantly higher (P < 0.001). Furthermore, NH600001 had a safety profile comparable to etomidate and elicited fewer myoclonus adverse events. In Conclusions, NH600001 has a sedative/anesthetic effect comparable to etomidate while reducing the risk of adrenocortical depression with a favorable safety profile. Chictr.org.cn identifier: ChiCTR2300069841, ChiCTR2400084095. Clinical Trial Number and Registry URL: NH60001-21, Identifier, ChiCTR2300069841 (Changsha, China;, principal investigator: Wen Ouyang, first registration date: March 28, 2023), https://www.chictr.org.cn; NH60001-31, Identifier, ChiCTR2400084095 (Changsha, China, principal investigator: Wen Ouyang, first registration date: May 10, 2024), https://www.chictr.org.cn.