Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration

doi:10.1016/j.clinthera.2020.12.012

	Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration
	Zhang, Yi-fan 1; Liu, Yan-mei 2,3; Yu, Chen 2,3; Wang, Ya-ting 2,3; Zhan, Yan 1; Liu, Hai-yan 4; Zou, Jian-jun 4; Jia, Jing-ying 2,3; Chen, Qian 2,3; Zhong, Da-fang 1
刊名	CLINICAL THERAPEUTICS
	2021-02-01
卷号	43 期号:2 页码:396-409
关键词	diabetes henagliflozin pharmacodynamics pharmacokinetics SGLT-2 inhibitors
ISSN号	0149-2918
DOI	10.1016/j.clinthera.2020.12.012
通讯作者	Chen, Qian(qchen@shxh-centerlab.com) ; Zhong, Da-fang(dfzhong@simm.ac.cn)
英文摘要	Background: Henagliflozin, a novel selective inhibitor of sodium-glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. Purpose: To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. Methods: Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5-200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25-100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. Findings: No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a T-max of 1.5-3 h, and then eliminated from plasma with a half-life of 11-15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5-200 mg (SAD) and 1.25-100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%-5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. (C) 2020 Published by Elsevier Inc.
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000636610200020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295200]
专题	中国科学院上海药物研究所
通讯作者	Chen, Qian; Zhong, Da-fang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 2.Shanghai Xuhui Cent Hosp, Shanghai, Peoples R China 3.Shanghai Engn Res Ctr Phase I Clin Res & Qual Con, Shanghai, Peoples R China 4.Jiangsu Hengrui Pharmaceut Co Ltd, Lianyungang, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Yi-fan,Liu, Yan-mei,Yu, Chen,et al. Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration[J]. CLINICAL THERAPEUTICS,2021,43(2):396-409.
APA	Zhang, Yi-fan.,Liu, Yan-mei.,Yu, Chen.,Wang, Ya-ting.,Zhan, Yan.,...&Zhong, Da-fang.(2021).Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration.CLINICAL THERAPEUTICS,43(2),396-409.
MLA	Zhang, Yi-fan,et al."Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration".CLINICAL THERAPEUTICS 43.2(2021):396-409.