title: Fed and Fasted Single-dose Assessment of Bioequivalence of Dapagliflozin and Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects.
abstract: OBJECTIVE
  In patients with type 2 diabetes mellitus, fixed-dose combinations (FDCs) of antihyperglycemic medications may provide complementary efficacy while reducing tablet burden and improving compliance. The aim of this study was to assess the bioequivalence and tolerability of 2 FDCs of dapagliflozin and metformin extended-release (XR) versus their individual component (IC) tablets.
  
  
  METHODS
  An open-label, balanced, randomized, 2-way crossover, 4-arm study was conducted in 129 healthy Brazilian subjects (aged 18-55 years). Two oral doses of the FDCs (5 mg dapagliflozin and 500 mg metformin XR, and 10 mg dapagliflozin and 1000 mg metformin XR) were evaluated in fed and fasted states.
  
  
  RESULTS
  Under fed and fasted conditions the 5 mg dapagliflozin and 500 mg metformin XR FDC showed bioequivalence to its ICs. The 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent to its ICs in fed subjects. Although AUC for the 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent in fasted subjects, the Cmax for metformin was not bioequivalent to its ICs in fasted subjects (upper 90% CI was 127.5%, and thus outside the 80%-125% bioequivalence interval). The small increase in the fasted state is not considered clinically meaningful due to the small magnitude of the difference (9.2%), the lack of metformin Cmax being associated with efficacy or tolerability concerns, and the fasted state not being the recommended state for dosing of metformin XR. The safety profile and tolerability of the FDCs were similar to those of their ICs and no deaths or serious adverse events were reported.
  
  
  CONCLUSIONS
  Both FDCs of dapagliflozin and metformin XR were bioequivalent to their ICs in fed and fasted subjects, except for the metformin Cmax from the 10 mg dapagliflozin and 1000 mg metformin XR FDC in fasted subjects. These data support the use of a dapagliflozin and metformin XR FDC in patients with type 2 diabetes mellitus.
authors.affiliation: AstraZeneca, Gaithersburg, Maryland. Electronic address: david.boulton2@astrazeneca.com.
authors.forename: David W
authors.initials: DW
authors.lastname: Boulton
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.affiliation: JDRF, New York, New York.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Griffen
authors.affiliation: Bristol-Myers Squibb, São Paulo, Brazil.
authors.forename: Catia
authors.initials: C
authors.lastname: Kitaura
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Susan
authors.initials: S
authors.lastname: Lubin
authors.affiliation: Bristol-Myers Squibb, Hopewell, New Jersey.
authors.forename: Allyson
authors.initials: A
authors.lastname: Pollack
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Frank
authors.initials: F
authors.lastname: LaCreta
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001938:Brazil; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D005215:Fasting; D005260:Female; D005960:Glucosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D013607:Tablets; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D005960:Glucosides; D007004:Hypoglycemic Agents; D013607:Tablets; C529054:dapagliflozin; D008687:Metformin
keywords: SGLT2 inhibitor; bioequivalence; dapagliflozin; fixed-dose combination; metformin extended release; type 2 diabetes mellitus