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INTRODUCTION: 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®). METHODS: 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 (Cmax), and area under the curve (AUC0-t). RESULTS: The 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. CONCLUSIONS: 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.
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Objectives: The objective of this study was to establish and validate an in vitro-in vivo correlation (IVIVC). To investigate the safety of a fixed-dose combination (FDC) versus the reference formulations (Januvia® 100 mg Filmtabletten co-administered with Glucophage® SR 1000 mg prolonged-release tablets), a bioequivalence study was conducted in the fasted and fed states, and the data generated were used to establish the correlation. Materials and Methods: The formulations used in the bioequivalence study were a FDC (sitagliptin hydrochloride equivalent to 100 mg of sitagliptin and metformin hydrochloride 1000 mg prolonged release) and Januvia® 100 mg co-administered with Glucophage® SR 1000 mg. The plasma profiles from the bioequivalence study and respective dissolution data were then utilized to establish "level A" IVIVC. The procedure comprises pharmacokinetic modeling to derive the empirical constants for further use in deconvolution and convolution procedures. Levy plots were constructed to understand the relationship between in vitro and in vivo properties. The internal and external predictabilities were evaluated by comparing the predicted pharmacokinetics with the observed values from the bioequivalence study. Results: The formulations showed approximately 91%-95% and 89%-91% dissolution, respectively in fasted and fed-state dissolution media for sitagliptin. The dissolution of metformin was 96%-98% and 89%-95%, respectively, in fasted and fed-state media. The regression coefficients of all the Levy plots were more than 0.900, indicating a linear correlation between in vitro release and in vivo parameters. The prediction error value of internal and external predictabilities was below 10 and met the US Food and Drug Administration criteria. Therefore, it can be stated that the correlation models are validated and can be used for predictions and to setting the dissolution specifications. The safety and tolerability of the FDC was found to be superior to those of the reference formulations, as fewer adverse events occurred following administration of the FDC. Conclusion: Correlation models can be useful for the prediction of FDCs during the management life cycle of the product. The models can also serve as a surrogate for in vivo studies. The FDC was tolerable, and the adverse events were mild and similar to those observed with the reference products. Therefore, the FDC is safe for use in human subjects.