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_cP, 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_cP (ΔΔQT_cP) 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_cP^avg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQT_cP 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.

DOI: 10.1111/j.1365-2125.2012.04416.x

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References