Kim Byungwook, Huh Ki Young, Hwang Jun Gi, Nah JaeJin, Huh Wan, Cho Jae Min, Jang In-Jin, Yu Kyung-Sang, Kim Yun, Lee SeungHwan
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Department of Clinical Pharmacology and Therapeutics, Chungbuk National University Hospital, Cheongju-si, Republic of Korea.
Br J Clin Pharmacol. 2023 Apr;89(4):1462-1470. doi: 10.1111/bcp.15613. Epub 2022 Dec 8.
DWP16001 is a novel sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes with selective and sustained sodium-glucose cotransporter 2 inhibition. We aimed to evaluate whether the coadministration of DWP16001 and metformin causes any changes in pharmacokinetics (PK) or pharmacodynamics (PD).
A randomized, open-label, single- and multiple-dose, 2-sequence, crossover study was conducted in healthy male subjects. Subjects received the following treatments: a single oral dose of DWP16001 (DWP) 2 mg, metformin immediate release 1000 mg (MET) twice daily for 7 days and a single oral dose of DWP and MET at steady-state for metformin (DWP+MET). Serial blood and interval urine were collected for PK and PD analyses. Safety and tolerability profiles were assessed throughout the study.
DWP+MET displayed increased peak concentration and area under the concentration-time curve from time 0 to time of the last quantifiable concentration compared with DWP (per standard bioequivalence boundaries, 0.8-1.25); the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were 1.22 (1.13-1.31) and 1.09 (1.05-1.14), respectively. DWP+MET and MET showed similar peak concentration and area under the concentration-time curve within a dosing interval at steady state for metformin; the GMRs and 90% CIs were 0.98 (0.90-1.06) and 1.05 (0.98-1.13), respectively. The amount of urinary glucose excretion from time 0 to 144 h was also comparable between DWP+MET and DWP (GMR and 90% CI; 0.99, 0.94-1.05).
The results suggest that DWP16001 and metformin could be coadministered without clinically relevant PK and PD interactions.
DWP16001是一种新型钠-葡萄糖协同转运蛋白2抑制剂，用于治疗2型糖尿病，具有选择性和持续性的钠-葡萄糖协同转运蛋白2抑制作用。我们旨在评估DWP16001与二甲双胍联合用药是否会引起药代动力学（PK）或药效学（PD）的任何变化。
在健康男性受试者中进行了一项随机、开放标签、单剂量和多剂量、2序列、交叉研究。受试者接受以下治疗：单次口服2 mg DWP16001（DWP），二甲双胍速释片1000 mg（MET），每日两次，共7天，以及在二甲双胍稳态时单次口服DWP和MET（DWP+MET）。采集系列血液和间隔尿液进行PK和PD分析。在整个研究过程中评估安全性和耐受性。
与DWP相比，DWP+MET在从0时间到最后可定量浓度时间的峰浓度和浓度-时间曲线下面积增加（根据标准生物等效性界限，0.8-1.25）；几何平均比值（GMR）及其90%置信区间（CI）分别为1.22（1.13-1.31）和1.09（1.05-1.14）。在二甲双胍稳态的给药间隔内，DWP+MET和MET的峰浓度和浓度-时间曲线下面积相似；GMR和90%CI分别为0.98（0.90-1.06）和1.05（0.98-1.13）。DWP+MET和DWP在0至144小时的尿葡萄糖排泄量也相当（GMR和90%CI；0.99，0.94-1.05）。
结果表明，DWP16001和二甲双胍可以联合给药，而不会产生临床相关的PK和PD相互作用。
