title: A thorough QT study of guanfacine.
abstract: OBJECTIVE
  Guanfacine extended- release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials. gov identifier: NCT00672984).
  
  
  METHODS
  In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediaterelease guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals.
  
  
  RESULTS
  In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours postdose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only 1-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common.
  
  
  CONCLUSIONS
  Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours postdose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
authors.forename: Lawrence
authors.initials: L
authors.lastname: Satin
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kahn
authors.forename: Antoine
authors.initials: A
authors.lastname: Robinson
authors.forename: Mary
authors.initials: M
authors.lastname: Corcoran
authors.forename: Jaideep
authors.initials: J
authors.lastname: Purkayastha
authors.forename: Sharon
authors.initials: S
authors.lastname: Youcha
authors.forename: James C
authors.initials: JC
authors.lastname: Ermer
mesh_terms: D000200:Action Potentials; D058647:Adrenergic alpha-2 Receptor Agonists / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D016316:Guanfacine / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D061214:Patient Safety; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D016316:Guanfacine