Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects. (15th March 2013)

• Record Type: Journal Article
• Authors: Darpö, Börje; Philip, Sager; MacConell, Leigh; Cirincione, Brenda; Mitchell, Malcolm; Han, Jenny; Huang, Wenying; Malloy, Jaret; Schulteis, Christine; Shen, Larry; Porter, Lisa
• Is Part Of: British journal of clinical pharmacology. Volume 75:Number 4(2013:Apr.)
• Page Start: 979
• Page End: 989
• Publication Date: 2013-03-15
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/j.1365-2125.2012.04416.x
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp4416-sec-0001" sec-type="section"> <title>Aims</title> <p>Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QT<sub>c</sub>) at therapeutic concentrations. This randomized, placebo‐ and positive‐controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QT<sub>c</sub>.</p> </sec> <sec id="bcp4416-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="bcp4416-sec-0003" sec-type="section"> <title>Results</title> <p>Targeted steady‐state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml<sup>−1</sup>, 399 ± 11.9 pg ml<sup>−1</sup> and 627 ± 21.2 pg ml<sup>−1</sup>). QT<sub>c</sub>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<sub>c</sub>P (ΔΔQT<sub>c</sub>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<sup>−1</sup> (ΔΔQT<sub>c</sub>P<sup>avg</sup>) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQT<sub>c</sub>P and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin.</p> </sec> <sec id="bcp4416-sec-0004" sec-type="section"> <title>Conclusions</title> <p>These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QT<sub>c</sub> and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.</p> </sec> </abstract>