Liu Yaxin, Kuang Yun, Huang Jie, Jiang Dan, Cao Yajie, Gao Qi, Li Zifeng, Ouyang Wen, Wang Saiying, Pei Qi, Yang Guoping
Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China.
Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, China.
AAPS J. 2024 Dec 21;27(1):21. doi: 10.1208/s12248-024-01004-7.
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.
NH600001是一种新型全身麻醉药，其结构与依托咪酯相似。本研究的目的是根据I-II期研究数据，探讨NH600001浓度与镇静效果之间的关系，以及影响NH600001药代动力学和药效动力学的因素。数据集包括2项针对健康受试者的I期研究和1项针对接受胃镜检查患者的II期研究。在建立NH600001的群体药代动力学和药效动力学（PopPK/PD）模型时使用了非线性混合效应建模。采用三室模型描述NH600001的药代动力学特征。参数用于基于体重的异速缩放，清除率的指数设为0.75，容积的指数设为1。盐酸阿芬太尼的联合使用影响中央室的分布容积和清除率。接受胃镜检查的患者（与健康受试者相比）对清除率、浅外周室的分布容积以及深外周室与中央室之间的室间清除率的影响被纳入最终的PopPK模型。效应室模型很好地描述了NH600001的PK/PD关系。模拟结果表明，初始剂量为0.25mg/kg的NH600001可导致快速镇静，每隔5分钟追加3次剂量可维持镇静超过20分钟。成功构建了健康受试者和接受胃镜检查患者的NH600001的PopPK/PD模型，可为即将开展的III期研究的给药方案提供参考。
