Schnaars Yvonne, Gaikwad Sumedh, Gottwald-Hostalek Ulrike, Klingberg Ulrike, Vadla Hari Kiran Chary, Prathap Vamshi Ramana
Merck KGaA, Frankfurter Str. 250, Post code F131 /001, 64293, Darmstadt, Germany.
Alfred E. Tiefenbacher GmbH & Co KG, Hamburg, Germany.
Diabetes Ther. 2022 Jun;13(6):1215-1229. doi: 10.1007/s13300-022-01269-1. Epub 2022 May 11.
Vildagliptin and metformin are two well-established oral antidiabetics with a complementary mechanism of action. Two new generic products, vildagliptin and its fixed-drug combination (FDC) with metformin, were tested for bioequivalence versus the approved originator reference products (Galvus® and Eucreas®).
Three randomized studies with two-treatment, two-period, two-sequence crossover design were conducted in healthy adults. One study evaluated vildagliptin 50 mg tablets as single dose under fasting conditions. Vildagliptin-metformin FDC tablet strengths of 50/850 mg and 50/1000 mg were evaluated in separate studies as single dose under fed conditions, given 30 min after a standardized high-fat, high-calorie breakfast following 10 h overnight fasting. Blood samples for analysis were collected until 24 h after dosing in each study period. Bioequivalence between test (T) and reference (R) products required 90% confidence interval (CIs) for the geometric least square (LS) mean T/R ratio to be within 80-125% for the pharmacokinetic parameters, maximum plasma concentration (C), and area under the curve (AUC).
The 90% CIs of geometric LS means of T/R ratio for C and AUC with vildagliptin tablets of 50 mg were 92.22-103.94% and 99.00-102.66%, respectively; corresponding results with FDC tablets for 50/850 mg tablets were 94.81-115.41% and 95.28-106.00% for vildagliptin and 90.87-101.18% and 90.56-100.09% for metformin; for 50/1000 mg tablets C and AUC were 105.56-122.30% and 98.30-107.55%, respectively, for vildagliptin and 92.14-103.73% and 94.60-101.81%, respectively, for metformin. Other parameters such as AUC, time to maximum concentration (T), and terminal half-life (t) were comparable between test and reference products. Adverse events (AEs), mainly vomiting, were reported without relevant difference between test and reference products in each study. AEs were generally mild and transient. No severe or serious AEs occurred.
The new generic drug products of vildagliptin and the FDCs of vildagliptin and metformin demonstrated bioequivalence to the approved originator products and are therefore expected to provide similar therapeutic effects.
维格列汀和二甲双胍是两种作用机制互补且已被广泛认可的口服抗糖尿病药物。对两种新的仿制药产品，即维格列汀及其与二甲双胍的固定剂量复方制剂（FDC），与已获批的原研参比产品（佳维乐®和欧唐宁®）进行了生物等效性测试。
在健康成年人中开展了三项采用双治疗、双周期、双序列交叉设计的随机研究。一项研究评估了50毫克维格列汀片剂在空腹条件下的单剂量情况。在单独的研究中，对50/850毫克和50/1000毫克的维格列汀 - 二甲双胍FDC片剂在进食条件下的单剂量进行了评估，在禁食10小时后，于标准化高脂、高热量早餐后30分钟给药。在每个研究周期内，直至给药后24小时采集血样进行分析。测试（T）产品与参比（R）产品之间的生物等效性要求药代动力学参数（最大血浆浓度（C）和曲线下面积（AUC））的几何最小二乘（LS）均值T/R比的90%置信区间（CI）在80 - 125%范围内。
50毫克维格列汀片剂的C和AUC的T/R比几何LS均值的90% CI分别为92.22 - 103.94%和99.00 - 102.66%；50/850毫克FDC片剂中，维格列汀的相应结果为94.81 - 115.41%和95.28 - 106.00%，二甲双胍为90.87 - 101.18%和90.56 - 100.09%；对于50/1000毫克片剂，维格列汀的C和AUC分别为105.56 - 122.30%和98.30 - 107.55%，二甲双胍分别为92.14 - 103.73%和94.60 - 101.81%。测试产品与参比产品之间的其他参数，如AUC、达峰时间（T）和末端半衰期（t）具有可比性。报告了不良事件（AE），主要为呕吐，各研究中测试产品与参比产品之间无相关差异。AE一般为轻度且短暂性。未发生严重或重大AE。
维格列汀新的仿制药产品以及维格列汀与二甲双胍的FDC制剂与已获批的原研产品具有生物等效性，因此预期能提供相似的治疗效果。
