Purpose: A fixed-dose combination (FDC) of gemigliptin/rosuvastatin 50/20 mg as a monolayer tablet has been used to treat patients with both type 2 diabetes mellitus and dyslipidemia. To improve the stability of the FDC, a new FDC formulation as a bilayer tablet was developed. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the FDC of gemigliptin/rosuvastatin 50/20 mg between the newly developed bilayer tablet and the approved monolayer tablet in healthy subjects.
Materials and Methods: A randomized, open-label, single-dose, two-treatment, two-way crossover study was conducted. Subjects received a single dose of the FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet or the monolayer tablet in each period with a 7-day washout. For PK and PD analyses, serial blood samples were collected up to 72 hours after dosing to determine plasma concentrations of gemigliptin, its active metabolite LC15-0636 and rosuvastatin, and plasma dipeptidyl peptidase-4 (DPP-4) activity. PK and PD parameters were calculated using non-compartmental methods and compared between the two formulations.
Results: A total of 48 healthy subjects were randomized, and 45 subjects completed the study. The concentration–time profiles of gemigliptin, LC15-0636 and rosuvastatin were comparable between the two formulations. All geometric mean ratios (90% confidence intervals) of the bilayer tablet to the monolayer tablet for maximum plasma concentration and area under concentration–time curve from 0 to last measurable time point of the three compounds fulfilled the bioequivalence criteria of 0.80– 1.25. Likewise, area under plasma DPP-4 activity inhibition from baseline-time curve from 0 to last measurable time point and maximum inhibition of plasma DPP-4 activity were similar between the two formulations.
Conclusion: The FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet showed equivalent PK and PD properties with the FDC of gemigliptin/rosuvastatin 50/20 mg as the monolayer tablet in healthy subjects. These results suggest that the newly developed bilayer tablet can become an alternative formulation to the commercially available monolayer tablet.

Keywords: DPP-4 inhibitor, statin, type 2 diabetes, dyslipidemia, bioequivalence


中文翻译：

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吉格列汀/瑞舒伐他汀 50/20 mg 固定剂量组合的两种制剂的药代动力学和药效学比较：一项随机、开放标签、单剂量、双向交叉研究

目的：吉格列汀/瑞舒伐他汀 50/20 mg 的固定剂量组合 (FDC) 作为单层片剂已用于治疗患有 2 型糖尿病和血脂异常的患者。为了提高 FDC 的稳定性，开发了一种新的 FDC 配方作为双层片剂。本研究旨在比较新开发的双层片和批准的单层片在健康受试者中的吉格列汀/瑞舒伐他汀 50/20 mg 的 FDC 的药代动力学 (PKs) 和药效学 (PDs)。
材料和方法：进行了一项随机、开放标签、单剂量、两次治疗、双向交叉研究。受试者在每个时期接受单剂量的吉格列汀/瑞舒伐他汀 FDC 50/20 mg 作为双层片剂或单层片剂，7 天清除。对于 PK 和 PD 分析，在给药后 72 小时内采集连续血样以确定吉格列汀、其活性代谢物 LC15-0636 和罗苏伐他汀的血浆浓度，以及血浆二肽基肽酶 4 (DPP-4) 活性。使用非隔室方法计算 PK 和 PD 参数并在两种制剂之间进行比较。
结果：共有 48 名健康受试者被随机分组​​，45 名受试者完成了研究。两种制剂的吉格列汀、LC15-0636 和罗苏伐他汀的浓度-时间曲线具有可比性。双层片与单层片的所有几何平均比率（90% 置信区间）对于三种化合物的最大血浆浓度和浓度-时间曲线下面积（从 0 到最后可测量时间点）均满足 0.80-1.25 的生物等效性标准。同样，从0到最后可测量时间点的基线时间曲线的血浆DPP-4活性抑制面积和血浆DPP-4活性的最大抑制在两种制剂之间相似。
结论：吉格列汀/瑞舒伐他汀 50/20 mg 作为双层片剂的 FDC 在健康受试者中显示出与吉格列汀/瑞舒伐他汀 50/20 mg 作为单层片剂的 FDC 相当的 PK 和 PD 特性。这些结果表明，新开发的双层片剂可以成为市售单层片剂的替代剂型。

关键词： DPP-4抑制剂，他汀类药物，2型糖尿病，血脂异常，生物等效性