Bioequivalence, Food Effect, and Steady-State Assessment of Dapagliflozin/Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects.

PURPOSE: Simplification of therapeutic regimens for patients with type 2 diabetes mellitus can provide convenience that leads to improved compliance. Dapagliflozin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the convenience of once-daily dosing. Two pharmacokinetic (PK) studies were conducted to establish bioequivalence for 2 doses of dapagliflozin/metformin XR FDC versus the same dosage of the individual component (IC) tablets in healthy adults. METHODS: Two open-label, randomized, 4-period, 4-arm crossover studies were conducted to assess the bioequivalence and PK properties of dapagliflozin and metformin FDCs in healthy subjects under fed and fasting conditions. Participants received single oral doses or once-daily dosing of dapagliflozin/metformin XR (5 mg/500 mg [study 1] or 10 mg/1000 mg [study 2]) for 4 days in an FDC formulation or corresponding strengths of IC tablets. FINDINGS: For both of the studies, dapagliflozin and metformin 5 mg/500 mg or 10 mg/1000 mg FDC tablets were bioequivalent to the respective IC tablets. The 90% CIs of the ratio of the adjusted geometric means for all key PK parameters (Cmax, AUC0-T, and AUC0-∞) were contained within the predefined 0.80 to 1.25 range to conclude bioequivalence for both dapagliflozin and metformin. Once-daily dosing to steady state of each FDC tablet had no effect on the PK properties of dapagliflozin or metformin. When the FDCs were administered with a light-fat meal, there was no effect on metformin PK values and only a modest, nonclinically meaningful effect on dapagliflozin PK values. There were no safety or tolerability concerns. IMPLICATIONS: Bioequivalence of the FDCs of dapagliflozin/metformin XR and the ICs was established, and no safety issues of clinical concern were raised.

Bioequivalence of saxagliptin/metformin immediate release (IR) fixed-dose combination tablets and single-component saxagliptin and metformin IR tablets in healthy adult subjects.

BACKGROUND: As compared with individual tablets, saxagliptin/metformin immediate release (IR) fixed-dose combination (FDC) tablets offer the potential for increased convenience, compliance, and adherence for patients requiring combination therapy. OBJECTIVES: Two bioequivalence studies assessed the fed-state and the fasted-state bioequivalence of saxagliptin/metformin IR 2.5 mg/500 mg FDC (study 1) and saxagliptin/metformin IR 2.5 mg/1,000 mg FDC (study 2) relative to the same dosage strengths of the individual component tablets [saxagliptin (Onglyza™) and metformin IR (Glucophage(®))] administered concurrently. STUDY DESIGNS: These were randomized, open-label, single-dose, four-period, four-treatment, crossover studies in healthy subjects (n = 24 in each study). The treatments in study 1 were a saxagliptin/metformin IR 2.5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 500 mg tablets co-administered in the fed state and fasted states on separate occasions. The treatments in study 2 were a saxagliptin/metformin IR 2.5 mg/1,000 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 1,000 mg co-administered in the fed state and fasted states on separate occasions. The pharmacokinetics, safety, and tolerability of each treatment were evaluated. RESULTS: For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components in both the fed and the fasted states as the limits of the 90 % confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within the predefined 0.800 to 1.250 bioequivalence criteria. Co-administration of saxagliptin and metformin IR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSIONS: Saxagliptin/metformin IR 2.5 mg/500 mg and saxagliptin/metformin IR 2.5 mg/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths in both the fed and the fasted states. No unexpected safety findings were observed with saxagliptin/metformin IR administration. The tolerability of the FDC of saxagliptin/metformin IR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin IR FDC tablets.