Type 2 diabetes mellitus (T2DM) is a complex metabolic disease with an increasing number of patients each year. [12] Sitagliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4), a newer treatment for type 2 diabetes mellitus. [13] Metformin hydrochloride is a biguanide, widely viewed as foundation therapy for type 2 diabetes mellitus. [14] More and more researches suggest that combination tablets will be an increasingly common strategy for the treatment of type 2 diabetes.[8] Sitagliptin Phosphate/metformin Hydrochloride Tablets is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide anti-hyperglycemic metformin which has become an important treatment for type 2 diabetes. [15] In this study, sitagliptin and metformin in plasma were quantitatively analyzed, and the pharmacokinetic characteristics and safety of domestic and original Sitagliptin Phosphate/metformin Hydrochloride Tablets were investigated, and the bioequivalence of the two preparations was evaluated. To provide multiple options for clinical combination regimens for type 2 diabetes.
Here, we assess the bioequivalence of Sitagliptin Phosphate/metformin Hydrochloride Tablets under fasting and fed conditions in healthy Chinese subjects following a single oral dose of 50mg/850mg test (Tonghua Dongbao Pharmaceutical Co., Ltd.) and reference (MSD Pharma (Singapore) Pte.Ltd) formulations. The two medicinal products are bioequivalent when their 90% CI of the AUC0 − t, AUC0−∞and Cmax of the reference preparation over the test preparation fall between the predetermined limits of 80 ~ 125%.
According to our results, both formulations were well tolerated, and no SAEs was observed during the study. All reported AEs were of mild intensity, and no subjects withdrew from the study because of any AEs. The main adverse drug reactions were nausea, hyperuricemia, and hyperkalemia. Most of the adverse drug reactions in this trial are similar to those reported in the literature, indicating that the test and reference formulations have good safety and tolerability in Chinese healthy subjects. [16] The reference formulations specifications and previous literature have reported that food can decrease metformin absorption and slightly delay it absorption.[17] The main pharmacokinetic parameters of oral reference formulations metformin in fed group were significantly lower than those of in fasting group, Cmax, AUC0 − t and AUC0−∞ were significantly lower. Metformin is usually recommended in meals to improve gastrointestinal tolerance. At the same time, food does not affect the PK of sitagliptin. Therefore, Sitagliptin Phosphate/metformin Hydrochloride Tablets are recommended for dietary administration.
In this study, the parameters such as recoveries, matrix effects, linear range, lower limit of quantification, stability by specificity, precision, and accuracy specifications, were investigated to confirm the method of LC-MS/MS. Concentration of sitagliptin and metformin in human plasma showed good linear relationship within 1-500 ng/mL and 3-1500 ng/mL. The relative standard deviation (RSD) values of intra- and inter-day precision were both less than 10%. As an open-label study, AEs assessment may not be objective enough. When the test formulation passes the evaluation and enters the market, the efficacy and side effects need to be further explored. In addition, as this study is designed as a bioequivalence trial, The pharmacokinetic parameters and characteristics were all healthy adults. Further studies are needed to obtain pharmacokinetic parameters and make a recommendation about the medication with the Sitagliptin Phosphate/metformin Hydrochloride Tablets in special populations.