title: The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses.
abstract: OBJECTIVE
  To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QT(c) interval in healthy subjects.
  
  
  METHODS
  The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QT(c) I) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained.
  
  
  RESULTS
  Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QT(c) I, at any time point. The placebo-corrected MCfB of QT(c) I was -1.1 (90% CI -2.7, 0.5) ms and -2.5 (-4.1, -0.9) ms for linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were ∼24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QT(c) I with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms.
  
  
  CONCLUSIONS
  Therapeutic and significantly supratherapeutic exposure to linagliptin is not associated with QT interval prolongation.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach/Riss, Germany. arne.ring@boehringer-ingelheim.com
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
authors.forename: Andreas
authors.initials: A
authors.lastname: Port
authors.forename: E Ulrike
authors.initials: EU
authors.lastname: Graefe-Mody
authors.forename: Ivette
authors.initials: I
authors.lastname: Revollo
authors.forename: Mario
authors.initials: M
authors.lastname: Iovino
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Dugi
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044465:White People; D055815:Young Adult
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin