Bioequivalence Evaluation in Healthy Volunteers: New Generic Formulations of Sitagliptin and Sitagliptin-Metformin Fixed-Dose Combination Compared with the Originator Products.

Abstract

Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850mg, 50/1000mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet. The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration-time curve from time 0 to last timepoint of measurable concentration (AUC0-t) and maximum plasma concentration (Cmax). Test (T) and reference (R) formulations proved bioequivalent if 90% confidence interval (CI) of geometric least-squares mean ratio for AUC0-t and Cmax were within BE acceptance range of 80.00-125.00%. Safety evaluations included vital signs, clinical laboratory tests, and adverse events (AEs). Treated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100mg), 26/25 (FDC 50/850mg), and 26/24 (FDC 50/1000mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUC0-t and Cmax were 95.83-100.37% and 91.85-109.56% (sitagliptin 100mg); 100.84-103.69% and 93.44-105.10% (FDC 50/850mg), and 101.26-105.20% and 98.71-112.89% (FDC 50/1000mg); respective values for metformin were 94.23-101.89% and 91.66-99.38% (FDC 50/850mg) and 98.45-104.89% and 96.79-105.62% (FDC 50/1000mg). All AEs were nonserious, transient, and mostly mild. Safety evaluations did not reveal any relevant difference between T and R formulations. The new generic tablet formulations of sitagliptin 100mg and the FDCs sitagliptin/metformin 50/850mg and 50/1000mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D). EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022).