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 & Quality Consistency Evaluation for Drugs, Shanghai, China.
Clin Ther. 2021 Sep;43(9):e264-e273. doi: 10.1016/j.clinthera.2021.07.008. Epub 2021 Aug 6.
Henagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of meal intake on the pharmacokinetic properties of henagliflozin, and to understand the excretion pathways of henagliflozin in humans.
In this Phase I, randomized, open-label, single-dose, two-period crossover study, 12 healthy male Chinese volunteers were randomized to receive either henagliflozin 10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition, or the reverse schedule, with the two administrations separated by a washout period of at least 7 days. Samples of blood, urine, and feces were collected and analyzed for the investigation of the pharmacokinetic profile and excretion pathways in the fasted and fed conditions. Any adverse events that occurred throughout the study were recorded for tolerability assessment.
After the administration of a single oral dose of henagliflozin, mean (SD) plasma AUC and C were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The fed/fasted ratios (90% CIs) of the geometric mean values of C, AUC, and AUC were 64% (54%-76%), 80% (76%-85%), and 80% (76%-85%), respectively. The median (range) T was prolonged from 1.5 (1-3) hours in the fasted condition to 2 (1.5-6) hours in the fed condition. Mass-balance testing revealed that henagliflozin was eliminated primarily as the parent drug in feces and as glucuronide metabolites in urine. In the fasted state, the cumulative excretion percentages of the parent drug and its metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values in the fed condition were changed to 50.4% and 25.5%, respectively. These findings suggest that postprandial administration decreases the absorption rate and the extent of henagliflozin exposure in humans, but has no effect on the metabolism or elimination of the drug.
In the present study, the consumption of a high-fat meal prior to henagliflozin administration was associated with reductions in AUC and C of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic findings on henagliflozin, this slight change may not have clinical significance. Mass balance of henagliflozin in humans was achieved with ∼75% of the administered dose recovered in excretions within 4 days after administration whether in the fasted or fed state. These findings suggest that henagliflozin tablets can be administered with or without food.
亨格列净是一种高度选择性和有效的钠-葡萄糖协同转运蛋白（SGLT）-2 抑制剂，用于治疗 2 型糖尿病（T2DM）患者。本研究旨在研究进食对亨格列净药代动力学特性的影响，并了解亨格列净在人体内的排泄途径。
这是一项在 12 名健康中国男性志愿者中进行的 I 期、随机、开放标签、单剂量、两周期交叉研究。志愿者被随机分为两组，一组在禁食条件下接受亨格列净 10mg，然后在进食条件下接受亨格列净 10mg；另一组则相反，两次给药之间有至少 7 天的洗脱期。采集血、尿和粪便样本，分析禁食和进食条件下的药代动力学特征和排泄途径。记录整个研究过程中发生的任何不良事件，以评估耐受性。
在单次口服给药后，在禁食状态下，亨格列净的平均（SD）血浆 AUC 和 C 分别为 1200（274）h·ng/mL 和 179（48.8）ng/mL，在进食状态下分别下降至 971（245）h·ng/mL 和 115（34.2）ng/mL。C、AUC 和 AUC 的几何均数比值（90%CI）分别为 64%（54%-76%）、80%（76%-85%）和 80%（76%-85%）。T 的中位数（范围）从禁食状态的 1.5（1-3）小时延长至进食状态的 2（1.5-6）小时。基于质量平衡测试，亨格列净主要以原形药物经粪便排泄，以葡萄糖醛酸代谢物经尿液排泄。在禁食状态下，原形药物及其代谢物的粪便累积排泄率分别为 40.6%和 33.9%；在进食状态下，这两个数值分别变为 50.4%和 25.5%。这些发现表明，餐后给药会降低亨格列净在人体内的吸收速率和暴露程度，但对药物的代谢或消除没有影响。
在本研究中，与空腹给药相比，进食高脂肪餐会导致 AUC 和 C 分别减少 19.4%和 36.4%。然而，基于对亨格列净药代动力学/药效学的分析，这种微小的变化可能没有临床意义。无论在禁食还是进食状态下，给药后 4 天内，约 75%的给药剂量以原形药物在粪便中排泄，在体内达到了质量平衡。这些发现表明，亨格列净片可以在进食或不进食时服用。
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