title: High-quality triplicate electrocardiogram monitoring in a first-in-man study: potential for early detection of drug-induced QT prolongation.
abstract: BACKGROUND
  QT interval prolongation is associated with an increased risk of potentially fatal ventricular tachycardias, including torsade de pointes. Regulatory guidance recommends the "thorough QT/QTc" (TQT) study as the gold standard for assessing the propensity of novel nonantiarrhythmic drugs to delay cardiac repolarization. An opportunity exists, however, to use high-quality electrocardiogram (ECG) data from first-in-man trials as an exploratory and complementary approach to gain early insight into potential risk of QT prolongation.
  
  
  METHODS
  We collected high-quality, triplicate, 12-lead ECG data during a first-in-man trial of a drug developed for the treatment of Type 2 diabetes that had shown in vitro hERG inhibition and potential to prolong QT intervals in an animal model.
  
  
  RESULTS
  QTc prolongation was observed at the highest dose, leading to a maximum QTcF prolongation > 19 ms at 6 hours after the 14th daily dose. QTcF increases from time-matched baseline relative to placebo were positively correlated with peak plasma concentrations.
  
  
  CONCLUSIONS
  Clinically relevant QT interval prolongations can be detected during first-in-man studies using high-quality ECG monitoring. Such data may facilitate early decision making on whether to terminate the development of a compound and invest resources in more promising molecules; and it may enable more efficient TQT study design or preclude the need for future TQT studies.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: He
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jing-He
authors.initials: JH
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Steven
authors.initials: S
authors.lastname: Komjathy
authors.forename: Ann
authors.initials: A
authors.lastname: Taylor
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; C000606913:KCNH2 protein, human; D043562:Receptors, G-Protein-Coupled