Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QT(c) interval in healthy subjects

AIMS: Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QT(c)) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QT(c). METHODS: Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. RESULTS: Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml(−1), 399 ± 11.9 pg ml(−1) and 627 ± 21.2 pg ml(−1)). QT(c)P, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QT(c)P (ΔΔQT(c)P) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml(−1) (ΔΔQT(c)P(avg)) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQT(c)P and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. CONCLUSIONS: These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QT(c) and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.