WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Linagliptin (BI 1356) is an oral, highly selective dipeptidyl peptidase-4 inhibitor which is under development for the treatment of type 2 diabetes mellitus and for which the pivotal phase III programme has recently been completed.
• There have been no observed electrocardiogram changes in a linagliptin single rising dose study with up to 600 mg, and no preclinical signals for QT liability.
WHAT THIS STUDY ADDS
• This manuscript describes the findings of a thorough QT study for linagliptin conducted according to the ICH E14 guideline, with a therapeutic dose (5 mg) and a 20-fold therapeutic dose (100 mg).
• Linagliptin does not cause clinically relevant changes of the corrected QT interval with a therapeutic dose and a 20-fold therapeutic dose.
• The 20-fold therapeutic dose of linagliptin was safe and well tolerated.
AIM To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QTc 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 (QTcI) 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 QTcI, at any time point. The placebo-corrected MCfB of QTcI 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 QTcI 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.