Abstract
IntroductionAlbiglutide, a selective once-weekly glucagon-like peptide-1 receptor agonist, is being developed for the treatment of type 2 diabetes mellitus. Albiglutide’s effect on cardiac repolarization (QTc interval) was assessed in a randomized, double-blind, placebo-controlled, parallel-group study in healthy subjects with a nested crossover comparison for moxifloxacin.MethodsSubjects were randomized to albiglutide (n = 85) or placebo (n = 89) and received injections of 30 mg albiglutide or placebo on Days 1 and 8 and 50 mg albiglutide or placebo on Days 15, 22, 29, and 36. In the placebo group, moxifloxacin was administered on Day −1 in half the subjects and on Day 40 in the other half. Blood samples for albiglutide plasma concentration were drawn on Days 4 and 39 and serial ECGs were extracted from continuous recordings on Days −2 (baseline), −1, 4, 39, and 40.ResultsDemographics were generally similar between albiglutide and placebo subjects: mean age was 29 years and BMI 25 kg/m2. Mean change-from-baseline QTcI (∆QTcI, which was corrected for individual heart rate) on Day 4 after a single dose of albiglutide 30 mg and on Day 39 after repeat dosing with albiglutide 50 mg once weekly was similar to the placebo response. The placebo-corrected ΔQTcI (ΔΔQTcI) on both albiglutide doses was small with the largest ΔΔQTcI of 1.1 ms (upper bound of 90% CI 3.8 ms) on Day 4 and −0.6 ms (upper bound of CI 1.8 ms) on Day 39. Moxifloxacin caused the largest mean effect on ΔΔQTcI of 10.9 ms and the lower bound of the CI was above 5 ms at all preselected timepoints, thereby demonstrating assay sensitivity. Albiglutide was well tolerated and there were no clinically relevant differences in safety data between albiglutide and placebo.ConclusionAlbiglutide at doses up to 50 mg in healthy subjects did not prolong the QTc interval.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-014-0055-1) contains supplementary material, which is available to authorized users.
Highlights
Albiglutide, a selective onceweekly glucagon-like peptide-1 receptor agonist, is being developed for the treatment of type 2 diabetes mellitus
After repeat dosing with albiglutide 50 mg once weekly, an increase in heart rate of approximately 6–8 bpm was observed (Table 1), whereas a single dose of albiglutide 30 mg was similar to placebo and moxifloxacin
A negative relation between albiglutide plasma levels and DDQTcI could be shown with a slope of -0.0003 ms/ng/ mL
Summary
Albiglutide, a selective onceweekly glucagon-like peptide-1 receptor agonist, is being developed for the treatment of type 2 diabetes mellitus. Albiglutide’s effect on cardiac repolarization (QTc interval) was assessed in a randomized, double-blind, placebo-controlled, parallel-group study in healthy subjects with a nested crossover comparison for moxifloxacin. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the E14 guidance in 2005 for clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs [5, 6]. A TQT study is typically conducted in healthy volunteers and should be placebo-controlled and designed to address potential bias, including the use of randomization and appropriate blinding. Moxifloxacin causes *7.5–18 ms QTc prolongation [7,8,9], and specific criteria have been established to confirm ‘‘assay sensitivity’’ with this drug in TQT studies [5]
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