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The DPP‐4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses
Author(s) -
Ring Arne,
Port Andreas,
GraefeMody E. Ulrike,
Revollo Ivette,
Iovino Mario,
Dugi Klaus A.
Publication year - 2011
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.03931.x
Subject(s) - linagliptin , qt interval , placebo , moxifloxacin , medicine , pharmacology , crossover study , anesthesia , diabetes mellitus , type 2 diabetes , endocrinology , antibiotics , chemistry , biochemistry , alternative medicine , pathology
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/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.