GST-HG171是一种有效的,广谱,口服生物可利用的小分子3C样(3CL)蛋白酶抑制剂,最近被批准用于治疗中国的轻中度冠状病毒病2019患者。由于细胞色素P450(CYP)酶,主要是CYP3A,是GST-HG171的主要代谢酶,肝损害可能会影响其药代动力学(PK)谱。旨在指导肝功能损害患者的临床用药,这项研究,使用非随机化的,开放标签,单剂量设计,评估肝功能损害对PK的影响,安全,和GST-HG171的耐受性。纳入轻度和中度肝功能损害患者以及健康受试者(n=8),接受单次口服剂量150mgGST-HG171,同时服用100mg利托那韦,以在GST-HG171给药之前和之后(-12、0、12和24小时)维持CYP3A抑制。与肝功能正常的受试者相比,GST-HG171的最大血浆浓度(Cmax)的几何最小二乘均值比(90%置信区间),浓度-时间曲线下的面积直至最后的可量化时间(AUC0-t),在轻度肝功能损害的受试者中,从时间0外推到无穷大(AUC0-∞)的血浆浓度-时间曲线下面积为1.14(0.99,1.31),1.07(0.88,1.30),和1.07(0.88,1.29),分别。对于中度肝功能损害,比率为0.87(0.70,1.07),0.82(0.61,1.10),和0.82(0.61,1.10),分别。肝功能损害未显著改变GST-HG171的峰值时间(Tmax)和消除半衰期(T1/2)。GST-HG171在研究中表现出良好的安全性和耐受性。一起来看,轻度至中度肝功能损害最小影响GST-HG171暴露,提示临床上轻中度肝功能损害患者无需调整GST-HG171剂量。临床试验在ClinicalTrials.gov(NCT06106113)注册。
GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in
China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled (n = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg
ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (-12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171\'s maximum plasma concentration (Cmax), area under the concentration-time curve up to the last quantifiable time (AUC0-t), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171\'s peak time (Tmax) and elimination half-life (T1/2). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic.Clinical TrialsRegistered at ClinicalTrials.gov (NCT06106113).