Huang Yunzhe, Liu Ran, Wang Yaqin, Liu Gege, Wang Changmao, Chen Xinyan, Jia Yuanwei, Shen Jie
School of Pharmacy, Wannan Medical College, Wuhu, Anhui, People's Republic of China.
Anhui Provincial Center of Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, People's Republic of China.
Clin Ther. 2022 Jul;44(7):945-956. doi: 10.1016/j.clinthera.2022.06.001. Epub 2022 Jun 28.
Hypertension is often observed in patients with diabetes, and the progression of diabetic nephropathy is closely related to blood pressure elevation. Thus, the effects of hypoglycemic drugs on kidney function and pharmacokinetic interactions in combination with antihypertensive and hypoglycemic drugs are of great clinical value. The purpose of this study was to evaluate the pharmacokinetic interactions between henagliflozin (SHR3824), a new sodium-dependent glucose transporter 2 (SGLT2) inhibitor class drug, and valsartan, an angiotensin II receptor blocker.
A single-center, single-arm, open-label, self-controlled study was conducted in healthy Chinese volunteers. The pharmacokinetic parameters were calculated with Phoenix WinNonlin version 7.0, and the statistical analysis was performed with SAS version 9.4. Data on pharmacokinetic parameters (single and/or steady-state) were collected and tabulated for different analytes (valsartan and SHR3824) according to the sampling time specified in the protocol. Continuous attention was paid to the safety of all subjects. The aim of the study was to evaluate the effect of a single dose of valsartan on the pharmacokinetic behavior of SHR3824 after multiple doses of SHR3824 (C and AUC) and the effect of multiple doses of SHR3824 on the pharmacokinetic behavior of valsartan (C, AUC, and AUC). A mixed effect model was used to estimate the point estimation and 90% CI of the geometric mean ratio of the corresponding pharmacokinetic indices at the combined-medication stage (SHR3824 + valsartan) and the single-medication stage (SHR3824 or valsartan).
Twelve volunteers were screened into this experiment and underwent blood sampling. The pharmacokinetic properties of SHR3824 were evaluated after its administration alone or in combination with valsartan. Point estimates and 90% CIs of the geometric mean ratio of SHR3824 C and AUC were within the conventional bioequivalence range of 80% to 125%. The pharmacokinetic properties of valsartan were evaluated after its administration alone or in combination with SHR3824. The geometric mean ratios and 90% CIs of the valsartan C, AUC, and AUC were also within the range of 80% to 125%. Thirty-four mild adverse events were reported, with no serious adverse events or suspected unexpected serious adverse reactions.
This study provides basis for the clinical co-administration of SHR3824 with angiotensin II receptor blockers represented by valsartan. Based on these findings, co-administration of SHR3824 and valsartan seemed to have no effect on the pharmacokinetic properties of either drug. Chinadrugtrials.org.cn Identifier: CTR20180002.
糖尿病患者常伴有高血压，糖尿病肾病的进展与血压升高密切相关。因此，降糖药物对肾功能的影响以及与降压和降糖药物联合使用时的药代动力学相互作用具有重要的临床价值。本研究旨在评估新型钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂类药物恩格列净（SHR3824）与血管紧张素II受体阻滞剂缬沙坦之间的药代动力学相互作用。
在健康中国志愿者中进行了一项单中心、单臂、开放标签、自身对照研究。使用Phoenix WinNonlin 7.0版计算药代动力学参数，并用SAS 9.4版进行统计分析。根据方案中规定的采样时间，收集不同分析物（缬沙坦和SHR3824）的药代动力学参数（单次和/或稳态）数据并制成表格。持续关注所有受试者的安全性。本研究的目的是评估单剂量缬沙坦对多次给药SHR3824后SHR3824的药代动力学行为（C和AUC）的影响，以及多次给药SHR3824对缬沙坦的药代动力学行为（C、AUC和AUC）的影响。使用混合效应模型估计联合用药阶段（SHR3824 + 缬沙坦）和单药治疗阶段（SHR3824或缬沙坦）相应药代动力学指标几何平均比值的点估计值和90%置信区间。
12名志愿者被纳入本实验并接受采血。评估了SHR3824单独给药或与缬沙坦联合给药后的药代动力学特性。SHR3824的C和AUC几何平均比值的点估计值和90%置信区间在80%至125%的传统生物等效性范围内。评估了缬沙坦单独给药或与SHR3824联合给药后的药代动力学特性。缬沙坦的C、AUC和AUC的几何平均比值及90%置信区间也在80%至125%的范围内。报告了34例轻度不良事件，无严重不良事件或疑似意外严重不良反应。
本研究为SHR3824与以缬沙坦为代表的血管紧张素II受体阻滞剂的临床联合用药提供了依据。基于这些发现，SHR3824与缬沙坦联合给药似乎对两种药物的药代动力学特性均无影响。中国临床试验注册中心标识符：CTR20180002。
