Background: Cardiovascular safety is important for antidiabetic agents. This study followed the ICH E14 guideline to examine the effect of the oral dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on the cardiac QT interval in healthy volunteers.
Methods: This thorough QT study of linagliptin was performed in healthy subjects, using 5 mg (therapeutic dose) and 100 mg. The randomised, single-dose, placebo-controlled, double-blind, four-way crossover study used open-label moxifloxacin (400 mg) as positive control. Triplicate 12-lead ECGs of 10 s duration were recorded for all subjects pre-dose and at various time points over a 24-h period after each treatment. The primary parameter was the subject-specific heart rate corrected QT interval (QTcI). Fourty-four subjects were enrolled, 26 (59.1%) of whom were male. The mean age was 36.4 (2248) years.
Results: After single oral administration of 5 and 100 mg linagliptin, geometric mean (gMean) maximum concentrations of 7.05 nmol/l (28.5% geometric coefficient of variation (gCV)) and 267 nmol/l (66.6% gCV) were reached at a median Tmax of 2 and 1.5 h, respectively. The upper limits of the two-sided 90% confidence intervals (CIs) of the adjusted mean QTcI change from baseline (14 h) of linagliptin compared with placebo were 0.5 ms (5 mg) and −0.9 ms (100 mg) with mean estimates of −1.1 and −2.5 ms, respectively. Over the 24 h observation period, the maximum upper limits of the one-sided 95% CIs for the adjusted QTcI changes from baseline compared with placebo were below 2.5 ms for both doses and thus well below the non-inferiority margin of 10 ms. Assay sensitivity of the trial was shown by the largest estimated effect size of the QTcI difference between moxifloxacin and placebo being 10.5 ms with a lower limit of the two-sided 90% CI of 8.1 ms. There were no relevant changes in heart rate or other ECG parameters, and the safety assessment was good and comparable for all treatments.
Conclusions: Single dose administration of therapeutic (5 mg) and supratherapeutic (100 mg) doses of linagliptin did not prolong the QT interval. The supratherapeutic dose resulted in maximum plasma concentrations that were about 38-fold higher than those obtained after the administration of the therapeutic dose of 5 mg, further confirming the very favourable safety profile of linagliptin within the DPP-4 inhibitors class.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology