Bioequivalence Studies of New Generic Formulations of Vildagliptin and Fixed-Drug Combination of Vildagliptin and Metformin Versus Respective Originator Products in Healthy Volunteers.

Abstract

IntroductionVildagliptin 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®).MethodsThree 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 (Cmax), and area under the curve (AUC0–t).ResultsThe 90% CIs of geometric LS means of T/R ratio for Cmax and AUC0–t 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 Cmax and AUC0–t 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 AUC0–∞, time to maximum concentration (Tmax), and terminal half-life (t1/2) 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.ConclusionsThe 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.