title: A randomized, open-label, crossover study evaluating the effect of food on the relative bioavailability of linagliptin in healthy subjects.
abstract: OBJECTIVE
  The objective of this study was to determine the relative bioavailability of the dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin when administered with and without food, in accordance with regulatory requirements to support dosing recommendations for patients.
  
  
  METHODS
  This was a randomized, open-label, crossover study involving 32 healthy white male and female subjects. All subjects received a single dose of 5 mg linagliptin after an overnight fast of at least 10 hours, or immediately after ingestion of a high-fat, high-calorie breakfast. These treatments were separated by a period of 5 weeks. Plasma samples for pharmacokinetic analysis were collected before dosing and at prespecified time points after dosing. The concentration of linagliptin in these samples was analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry. Relative bioavailability was assessed by the total area under the curve between 0 and 72 hours (AUC(0-72)) and maximum measured plasma concentration (C(max)) of linagliptin. Tolerability was also assessed.
  
  
  RESULTS
  In 32 subjects (mean age, 34.8 years; weight, 74.3 kg; male, 53%; white race, 100%), intake of a high-fat meal resulted in comparable bioavailability with regard to AUC(0-72) (geometric mean ratio [GMR] between the fed and fasted group means was 103.5%; 90% CI, 98.1%-109.2%). Individuals' responses to food ranged from a maximum increase in exposure of 38% to a decrease of 32% relative to the fasted state. The concurrent intake of food increased the time to reach maximum plasma concentration (T(max)) by approximately 2 hours and reduced C(max) by about 15% (GMR 84.7%; 90% CI, 75.9%-94.6%). Since adequate drug exposure for inhibition of DPP-4 was still given for the entire 24-hour dosing interval, this result was considered to be of no clinical relevance. Linagliptin was well tolerated during the study.
  
  
  CONCLUSIONS
  Intake of a high-fat meal reduced the rate of linagliptin absorption but had no influence on the extent of absorption; this finding suggests that food has no relevant influence on the efficacy of linagliptin.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. Ulrike.Graefe-Mody@boehringer-ingelheim.com
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graefe-Mody
authors.forename: Thomas
authors.initials: T
authors.lastname: Giessmann
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
authors.forename: Mario
authors.initials: M
authors.lastname: Iovino
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin