Cheng Yuanzhi, Hu Xiaotong, Pei Zejun, Zhang Zhe, Lin Hongda, Feng Sheng, Gao Zhenyan, Ma Yanlin, Cao Zhihai, Zhang Qian, Zheng Liang, Zhang Wei, Shen Kai, Hu Wei
Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Department of Clinical Pharmacology, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.
Expert Opin Drug Metab Toxicol. 2025 Jan-Feb;21(2):217-224. doi: 10.1080/17425255.2024.2428367. Epub 2024 Nov 14.
SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam.
In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC, AUC, and C).
The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%.
SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile.
www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).
SHR4640是一种高选择性尿酸转运蛋白1（URAT1）抑制剂，在体内临床试验中对其抑制细胞色素P450 2C8（CYP2C8）和细胞色素P450 3A4（CYP3A4）的作用进行了评估。本研究评估了SHR4640与CYP2C8探针底物瑞格列奈以及CYP3A4探针底物咪达唑仑合用时的药代动力学（PK）影响。
在这项单中心、随机、双盲、安慰剂对照研究中，参与者按1:1:1的比例随机分配至SHR4640 A组、SHR4640 B组和安慰剂组，并在特定时间口服瑞格列奈、咪达唑仑、SHR4640或安慰剂。主要终点包括瑞格列奈和咪达唑仑单独使用以及与SHR4640合用时的主要PK参数（曲线下面积[AUC]、AUC和峰浓度[C]）。
与SHR4640合用时，瑞格列奈的浓度 - 时间曲线下面积（AUC）增加小于1.25倍，而咪达唑仑的AUC略有增加，为46%。
SHR4640对CYP酶探针底物的AUC具有微弱抑制作用，药物 - 药物相互作用潜力极小，安全性良好。
www.clinicaltrials.gov标识符为NCT06196580（名称：SHR4640对瑞格列奈和咪达唑仑的PK影响以及SHR4640对QT间期的影响）
