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Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QT c interval in healthy subjects
Author(s) -
Darpö Börje,
Philip Sager,
MacConell Leigh,
Cirincione Brenda,
Mitchell Malcolm,
Han Jenny,
Huang Wenying,
Malloy Jaret,
Schulteis Christine,
Shen Larry,
Porter Lisa
Publication year - 2013
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.1365-2125.2012.04416.x
Subject(s) - exenatide , qt interval , placebo , medicine , moxifloxacin , heart rate , confidence interval , crossover study , population , anesthesia , cardiology , pharmacology , diabetes mellitus , type 2 diabetes , endocrinology , blood pressure , chemistry , biochemistry , alternative medicine , environmental health , pathology , antibiotics
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 (ΔΔ QT 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 (ΔΔ QT c P avg ) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔ QT 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.