title: Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects.
abstract: OBJECTIVE
  Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc ) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc .
  
  
  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) ). QTc 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 QTc P (ΔΔQTc 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) (ΔΔQTc P(avg) ) was -1.13 [-2.11, -0.15). No correlation was observed between ΔΔQTc P and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin.
  
  
  CONCLUSIONS
  These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.
authors.affiliation: Department of Clinical Science and Education, Section of Cardiology, Karolinska Institute, Stockholm, Sweden. borje.darpo@telia.com
authors.forename: Börje
authors.initials: B
authors.lastname: Darpö
authors.forename: Philip
authors.initials: P
authors.lastname: Sager
authors.forename: Leigh
authors.initials: L
authors.lastname: MacConell
authors.forename: Brenda
authors.initials: B
authors.lastname: Cirincione
authors.forename: Malcolm
authors.initials: M
authors.lastname: Mitchell
authors.forename: Jenny
authors.initials: J
authors.lastname: Han
authors.forename: Wenying
authors.initials: W
authors.lastname: Huang
authors.forename: Jaret
authors.initials: J
authors.lastname: Malloy
authors.forename: Christine
authors.initials: C
authors.lastname: Schulteis
authors.forename: Larry
authors.initials: L
authors.lastname: Shen
authors.forename: Lisa
authors.initials: L
authors.lastname: Porter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D001372:Aza Compounds / Q000009:adverse effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D000077270:Exenatide; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D011804:Quinolines / Q000009:adverse effects; D014688:Venoms / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood
chemical_list: D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D007004:Hypoglycemic Agents; D010455:Peptides; D011804:Quinolines; D014688:Venoms; D000077270:Exenatide; D000077266:Moxifloxacin