Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Proline Henagliflozin in Chinese Subjects with Varying Degrees of Liver Dysfunction

• Published in: Journal of clinical pharmacology Vol. 64; no. 8; p. 1015
• Main Authors: Ding, Likun, Yang, Lin, Ren, Danjun, Gao, Xiaohua, Zhang, Juanli, Liu, Meiyou, Sun, Li, Diao, Qingbo, Feng, Sheng, Wen, Aidong, Wang, Jingwen
• Format: Journal Article
• Language: English
• Published: England 01.08.2024
• Subjects: Adult; Area Under Curve; Asian People; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Diabetes Mellitus, Type 2 - drug therapy; East Asian People; Female; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Liver Diseases - metabolism; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors - adverse effects; Sodium-Glucose Transporter 2 Inhibitors - pharmacokinetics; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Young Adult; pharmacokinetics; type 2 diabetes mellitus; proline henagliflozin; liver dysfunction; pharmacodynamics; safety
• ISSN: 1552-4604
• DOI: 10.1002/jcph.2437

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (U ) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population.