title: Linagliptin fixed-dose combination with metformin is bioequivalent to co-administration of linagliptin and metformin as individual tablets.
abstract: OBJECTIVE
  To demonstrate bioequivalence of linagliptin/metformin fixed-dose combination (FDC) tablets and the corresponding combination of individual tablets taken together, i.e., free-pill (FP) treatment.
  
  
  METHODS
  Three dosing combinations were evaluated in three separate randomized studies: linagliptin 2.5 mg with 500 mg, 850 mg, or 1,000 mg metformin. These studies used a prospective, open-label, randomized, two-way crossover design to evaluate bioequivalence in healthy volunteers (n = 287). After an overnight fast, participants received an FDC tablet once, and on a separate visit received the corresponding FP treatment. The two possible treatment sequences (FDC/FP and FP/FDC) were randomly allocated to the participants. A washout period of 35 days separated the two study treatments. The primary endpoints were maximum plasma concentration (Cmax) of linagliptin and metformin, area under the plasma concentration time curve from 0 to 72 hours (AUC0-72) for linagliptin, and from 0 to infinity (AUC0-inf) for metformin.
  
  
  RESULTS
  The 90% confidence intervals of the adjusted geometric mean ratios of Cmax and AUC (calculated as FDC/ FP) were within the bioequivalence acceptance limits of 80 - 125%. The number of participants reporting at least one adverse event following FDC treatments was comparable to, or less than, that following FP treatments. Evaluation of vital signs and clinical laboratory tests revealed no safety issues.
  
  
  CONCLUSIONS
  FDC tablets of linagliptin and metformin are bioequivalent to individual tablets of respective dose strengths taken together. Both treatments were well tolerated.
authors.forename: Susanne
authors.initials: S
authors.lastname: Buschke
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
authors.forename: Christian
authors.initials: C
authors.lastname: Friedrich
authors.forename: Katrin
authors.initials: K
authors.lastname: Metzmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinicke
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D000069476:Linagliptin; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D011446:Prospective Studies; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013607:Tablets; D013810:Therapeutic Equivalency
chemical_list: D004338:Drug Combinations; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D013607:Tablets; D000069476:Linagliptin; D008687:Metformin