State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Shanghai Xuhui Central Hospital, Shanghai, China; Shanghai Engineering Research Center of Phase I Clinical Research and Quality Consistency Evaluation for Drugs, Shanghai, China.
Clin Ther. 2021 Feb;43(2):396-409. doi: 10.1016/j.clinthera.2020.12.012. Epub 2021 Jan 14.
Henagliflozin, a novel selective inhibitor of sodium-glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus.
To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers.
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.
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 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.
Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.
Henagliflozin 是一种新型选择性钠-葡萄糖共转运蛋白 2 抑制剂，目前正在开发用于治疗 2 型糖尿病。
评估 Henagliflozin 在健康中国志愿者中的耐受性、药代动力学（PK）和药效学（PD）特征。
进行了两项临床研究。一项是单剂量递增（SAD）研究（2.5-200mg），涉及 80 名健康受试者；另一项是多剂量递增（MAD）研究（1.25-100mg，连续 10 天），涉及 48 名健康受试者。这两项研究中，对 Henagliflozin 的耐受性、PK 特征及其主要代谢物、24 小时内尿糖排泄情况进行了描述。
健康受试者单次和多次口服 Henagliflozin 后未观察到严重不良事件，表明该药具有良好的耐受性。Henagliflozin 吸收迅速，T1/2 为 1.5-3 小时，半衰期为 11-15 小时，血浆中消除缓慢。每日口服一次不蓄积。SAD 和 MAD 研究中，Henagliflozin 的暴露量与剂量呈比例关系，剂量范围分别为 2.5-200mg 和 1.25-100mg。Henagliflozin 在尿液中的排泄率非常低，仅占剂量的 3.00%-5.13%。在血浆样品中检测到的主要代谢物为 M5-1、M5-2 和 M5-3，在稳态时分别占母体药物的 54.3%、19.8%和 27.5%。SAD 和 MAD 研究均表明，24 小时尿糖排泄量随剂量增加呈剂量依赖性增加，并在 >25mg 时呈现饱和动力学。Henagliflozin 单次或多次给药后，血清葡萄糖和尿液电解质水平无明显变化。
Henagliflozin 在这些健康受试者中具有良好的耐受性，表现出可预测的 PK/PD 特征。Henagliflozin 不影响血糖水平或尿电解质排泄。每日一次，最大剂量 25mg 时最佳。中国临床试验注册中心注册号：CTR20131986 和 CTR20140132。
