022: Pharmacokinetics of a Fixed-dose Combination of Dapagliflozin 10 mg & Sitagliptin 100 mg for the Treatment of Type 2 Diabetes Mellitus

Statement of Purpose: Diabetes is a progressive disease that requires sustained intensive therapy to maintain adequate glycemic control. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and sitagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, have been shown to be well tolerated and efficacious for the treatment of type 2 diabetes mellitus (T2DM) when co-administered (as their individual components), consistent with their complementary mechanisms of action (Jabbour et al. Diabetes Care. 2014;37:740-750). Furthermore, their co-administration has been shown to not be associated with any pharmacokinetic drug-drug interactions (Kasichayanula et al. Diabetes Obes Metab. 2011;13:47-54). A dapagliflozin/sitagliptin fixed-dose combination (FDC) product could contribute to management of T2DM by providing efficient glucose control with more patients reaching therapeutic goals without increased risk of hypoglycemia or weight gain. We evaluated pharmacokinetics in healthy adults to compare the pharmacokinetic profiles and tolerability and to assess bioequivalence of a 10 mg dapagliflozin/100 mg sitagliptin FDC tablet (test formulation) and dapagliflozin (10 mg) plus sitagliptin (100 mg) co-administered as individual tablets (reference formulation).

Description of Methods & Materials: A single center, randomized, open-label, 2-period, 2-treatment, single dose, crossover study was conducted in healthy subjects (men and women) aged 18–55 years and with a BMI between 18.5 and 30 kg/m². Safety and tolerability were assessed via adverse events, vital signs, physical examination, 12-lead ECG and clinical laboratory tests. Subjects were randomized to receive a single oral dose of the formulations (test followed by reference, or vice versa) under fasted conditions. Each treatment period was separated by a washout period of at least 7 days. Serial blood samples (pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36 and 72 hours post-dose) were collected for both dapagliflozin and sitagliptin. Primary pharmacokinetic endpoints included C_max, AUC_last and AUC_inf.

Data & Results: A total of 46 subjects were randomized and 43 were included in the pharmacokinetic and bioequivalence evaluation. The mean age was 39.5 years, 60.9% were men, and 87.0% were White, with the remainder Black (4.3%), Asian (2.2%) or other (6.5%). The 90% confidence intervals for the geometric least-squares mean ratios for C_max, AUC_last and AUC_inf (test formulation vs reference formulation) were within the bioequivalence range of 0.80 to 1.25 for both formulations, demonstrating bioequivalence (Table). The FDC and individual mono components were well tolerated by all subjects.

Interpretation, Conclusion or Significance: Dapagliflozin (10 mg) and sitagliptin (100 mg), when administered as a FDC tablet or co administered as individual tablets, were found to be bioequivalent in healthy adults. These findings support the use of dapagliflozin/sitagliptin FDC in patients with T2DM. No new safety signals were identified. FDC treatment option enables a reduced pill burden, thereby increasing patient convenience and potentially improving compliance.

Disclosures: Clinical trial identifiers: NCT05266404 Study sponsor: AstraZeneca Conflicts of interest disclosures Pradeep B. Lukka, Weifeng Tang, Ann Hammarstedt, Cecilia Karlsson, Tom Conrad and David W. Boulton are employees of AstraZeneca. Pradeep B. Lukka, Weifeng Tang, Ann Hammarstedt, Cecilia Karlsson and David W. Boulton are shareholders of AstraZeneca.