Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects.
ABSTRACT As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer potential for increased patient compliance with the convenience of once-daily dosing. Two bioequivalence studies assessed the fed-state bioequivalence of saxagliptin/metformin XR 5 mg/500 mg FDC (study 1) and saxagliptin/metformin XR 5 mg/1000 mg FDC (study 2) relative to the same dosage strengths of individual component tablets administered concurrently. The effect of food on saxagliptin and metformin pharmacokinetics from the saxagliptin/metformin XR 5 mg/500 mg FDC and their steady-state pharmacokinetics from the saxagliptin/metformin XR 5 mg/1000 mg were also investigated.
These were randomized, open-label, single-dose, three-period, three-treatment, crossover studies in healthy subjects (n = 30 in each study). The treatments in study 1 were a saxagliptin/metformin XR 5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 5 mg and metformin XR 500 mg co-administered in the fed state. The treatments in study 2 were a saxagliptin/metformin XR 5 mg/1000 mg FDC tablet in the fed state, saxagliptin 5 mg and 2 × metformin XR 500 mg co-administered in the fed state, and saxagliptin/metformin XR 5 mg/1000 mg FDC once daily for 4 days in the fed state to assess steady-state pharmacokinetics. The safety and tolerability of each treatment were also evaluated.
For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components as the limits of the 90% confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within 0.800 to 1.250. Compared with the fasted state, food did not have a meaningful effect on the pharmacokinetics of saxagliptin and metformin when administered as the saxagliptin/metformin XR 5 mg/500 mg FDC. The saxagliptin/metformin XR 5 mg/1000 mg FDC showed consistent pharmacokinetics at steady state without evidence of dose dumping. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets.
Saxagliptin/metformin XR 5 mg/500 mg and saxagliptin/metformin XR 5 mg/1000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths. Additionally, food had little effect on the pharmacokinetics of saxagliptin and metformin administered in the saxagliptin/metformin XR 5 mg/500 mg FDC and the steady-state pharmacokinetics of the saxagliptin/metformin XR 5 mg/1000 mg FDC was consistent over time. No unexpected safety findings were observed with saxagliptin/metformin XR administration. The tolerability of the FDC of saxagliptin/metformin XR 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 XR FDC tablets.
ClinicalTrials.gov Identifiers: NCT01192139 and NCT01192152.
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ABSTRACT: Saxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes. This was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18-65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period. Mean (range) baseline HbA1C was 7.4% (6.4-9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity. Once daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.Diabetes therapy : research, treatment and education of diabetes and related disorders. 10/2013;
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ABSTRACT: The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have demonstrated that the combination therapy of DPP-4 inhibitors and metformin (as an add-on, an initial combination, or a fixed-dose combination) provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 via increasing GLP-1 secretion, suppressing activity of DPP-4, and upregulating the expression of GLP-1 receptor in pancreatic β cells. Conversely, DPP-4 inhibitors have a favorable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin.Diabetes Obesity and Metabolism 05/2013; · 5.18 Impact Factor
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ABSTRACT: Fixed-dose combination (FDC) products represent a widely accepted approach to type 2 diabetes treatment, given that monotherapies sometimes fail to meet the treatment targets - obtaining a sustained reduction in micro- and macrovascular complications. Saxagliptin (SAXA)/metformin (MET) FDC tablets can be used either alone or in combination with glyburide, thiazolidinediones, or insulin. It has been proven that the SAXA/MET combination leads to a significant improvement in glycemic control compared to placebo in patients with type 2 diabetes that is inadequately controlled with MET alone. In addition, this FDC has been proven to be safe for people with diabetes mellitus and established cardiovascular disease, elderly patients, and patients with impaired renal function (>30 mL/minute), with dosage modification. Patient compliance, adherence, and persistence to the therapeutic regimen has been shown to be very good, while the titration of each compound according to the patient's profile is easy, given the availability of different formulations. The SAXA/MET FDC is a patient-friendly, dosage-flexible, and hypoglycemia-safe regimen with very few adverse events and a neutral or even favorable effect on body weight. It achieves significant glycosylated hemoglobin A1c reduction helping the patient to achieve his/her individual glycemic goals.Patient Preference and Adherence 01/2014; 8:227-236. · 1.33 Impact Factor