title: Lomitapide at supratherapeutic plasma levels does not prolong the Qtc interval--results from a TQT study with moxifloxacin and ketoconazole.
abstract: BACKGROUND
  The aim of this study was to assess the effect of high plasma levels of lomitapide and its main metabolite on ECG parameters.
  
  
  METHODS
  In this randomized five-way cross-over thorough QT study, 56 healthy subjects were enrolled. Study treatments were administered orally for 3 days in five separate periods in which subjects were dosed with (1) a single dose of 75 mg lomitapide on Day 1 followed by a single dose of 200 mg on Day 3; (2) ketoconazole 200 mg BID; (3) ketoconazole with a single dose of 75 mg lomitapide on Day 3; (4) a single dose of 400 mg moxifloxacin on Day 3 and (5) placebo.
  
  
  RESULTS
  Single doses of 75 and 200 mg lomitapide alone or in combination with ketoconazole caused minor changes in the change-from-baseline QTcI (ΔQTcI), whereas moxifloxacin and ketoconazole caused an increase of ΔQTcI with a peak effect at 1 and 3 hours postdosing, respectively. The largest mean placebo-corrected ΔQTcI (ΔΔQTcI) for lomitapide did not exceed 3 ms (upper bound of 90% CI: 4.7 ms) at any time points postdosing. Ketoconazole caused mild QT prolongation with mean ΔΔQTcI of 5.9 and 6.5 ms at 2 and 3 hours postdosing, and exposure-response analysis demonstrated a significantly positive slope of 1.3 ms per μg/mL (90% CI: 1.0-1.7). Moxifloxacin met the criteria for assay sensitivity.
  
  
  CONCLUSIONS
  Lomitapide does not have an effect on cardiac repolarization. The study's ability to detect small QTc changes was demonstrated with both moxifloxacin and ketoconazole.
authors.affiliation: iCardiac Technologies, Rochester, NY; Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Georg
authors.initials: G
authors.lastname: Ferber
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
authors.forename: Mark
authors.initials: M
authors.lastname: Sumeray
authors.forename: Philip
authors.initials: P
authors.lastname: Sager
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D001372:Aza Compounds / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000494:pharmacology*; D012016:Reference Values; D013997:Time Factors; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D055815:Young Adult
chemical_list: D058888:14-alpha Demethylase Inhibitors; D001372:Aza Compounds; C473731:BMS201038; D001562:Benzimidazoles; D024841:Fluoroquinolones; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D007654:Ketoconazole; D000077266:Moxifloxacin
keywords: QT/QTc; healthy volunteers; ketoconazole; lomitapide; thorough QT study