title: Fixed-dose combination tablet of repaglinide and metformin is bioequivalent to concomitantly administered individual tablets of repaglinide and metformin : randomized, single-blind, three-period crossover study in healthy subjects.
abstract: OBJECTIVE
  Repaglinide and metformin enhance insulin secretion and decrease hepatic gluconeogenesis, respectively, and are commonly coadministered as separate formulations to treat patients with type 2 diabetes mellitus. A single combination therapy tablet offers increased patient convenience and the subsequent potential for increased therapy compliance. The aim of this randomized, single-blind, three-period crossover study was to determine the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations. Secondary objectives included a comparison of the dose proportionality of an FDC tablet of repaglinide/metformin 1 mg/500 mg and an FDC tablet of repaglinide/metformin 2 mg/500 mg, as well as the safety and tolerability of repaglinide and metformin in combination tablet therapy.
  
  
  METHODS
  Healthy subjects (n = 93, age 18-45 years) were randomized to one of six possible treatment sequences (Williams design) of an FDC tablet of repaglinide/metformin 2 mg/500 mg, repaglinide 2 mg and metformin 500 mg coadministered as separate tablets and an FDC of repaglinide/metformin 1 mg/500 mg. Fifty-five subjects completed the study. Four primary pharmacokinetic endpoints (area under the plasma concentration-time curve [AUC] from time 0 hours to infinity; AUC from time 0 to 24 hours; AUC from time 0 hours to time t [the last time of measurable concentration after dosing]; and the maximum plasma concentration) were used to assess bioequivalence and dose proportionality. The safety and tolerability of repaglinide and metformin in combination tablet therapy were also evaluated.
  
  
  RESULTS
  Both repaglinide and metformin in the combination tablet were determined to be bioequivalent to the individual tablets of repaglinide 2 mg and metformin 500 mg, as the limits of the 90% confidence interval of the mean treatment ratio for all pharmacokinetic parameters were contained within the pre-specified interval required for bioequivalence (0.8, 1.25). Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to an FDC of repaglinide/metformin 1 mg/500 mg for all analysed endpoints. No withdrawals as a result of adverse events occurred during this study. In addition, no clinically relevant abnormalities were found during physical examinations, in vital signs, ECG parameters or clinical laboratory parameters.
  
  
  CONCLUSIONS
  An FDC tablet of repaglinide/metformin 2 mg/500 mg was bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg. Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was dose proportional to an FDC tablet of repaglinide/metformin 1 mg/500 mg. Finally, no unexpected safety concerns were noted with repaglinide/metformin combination tablet therapy. Our results suggest that FDC tablets of repaglinide and metformin would provide safety and efficacy comparable to that of repaglinide and metformin administered as separate formulations.
authors.affiliation: Pharmaceutical Product Development, Limited Partnership, Austin, Texas 78744, USA. dhoelscher@mac.com
authors.forename: David
authors.initials: D
authors.lastname: Hoelscher
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chu
authors.forename: William
authors.initials: W
authors.lastname: Lyness
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018401:Sample Size; D016037:Single-Blind Method; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D002219:Carbamates; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D010880:Piperidines; C072379:repaglinide; D008687:Metformin