title: Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects.
abstract: OBJECTIVE
  To characterize the effects of lamotrigine on QT interval in healthy subjects.
  
  
  METHODS
  Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic-pharmacodynamic (PK-PD) modelling.
  
  
  RESULTS
  Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo -7.48 ms, 90% CI -10.49, -4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK-PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied.
  
  
  CONCLUSIONS
  Therapeutic doses of lamotrigine (50-200 mg b.d.) were not associated with QT prolongation in healthy subjects.
authors.affiliation: Department of Clinical Pharmacology and Discovery Medicine, Discovery Biometrics, GlaxoSmithKline, Harlow, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Dixon
authors.forename: Sarah
authors.initials: S
authors.lastname: Job
authors.forename: Ruth
authors.initials: R
authors.lastname: Oliver
authors.forename: Debra
authors.initials: D
authors.lastname: Tompson
authors.forename: John G
authors.initials: JG
authors.lastname: Wright
authors.forename: Kay
authors.initials: K
authors.lastname: Maltby
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lorch
authors.forename: Jorg
authors.initials: J
authors.lastname: Taubel
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000379:methods*; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D000077213:Lamotrigine; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000889:Anti-Arrhythmia Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D014227:Triazines; D000077266:Moxifloxacin; D000077213:Lamotrigine