title: A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects.
abstract: OBJECTIVE
  Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance.
  
  
  METHODS
  This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo.
  
  
  RESULTS
  Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were </=10 milliseconds greater than the corresponding reference at all postdose time points under conditions of both therapeutic and supratherapeutic plasma concentrations of neratinib. Pharmacokinetic/pharmacodynamic analysis revealed no relationship between neratinib concentrations and QTc interval. No subjects had QTcI, QTcF, or QTcN intervals >450 milliseconds or change from baseline >30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P < 0.05).
  
  
  CONCLUSIONS
  Therapeutic and supratherapeutic plasma concentrations of neratinib do not prolong the QTc interval in healthy subjects.
authors.affiliation: Department of Clinical Pharmacology, Pfizer Inc., 500 Arcola Road, Collegeville, PA 19426, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Hug
authors.forename: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Cathie
authors.initials: C
authors.lastname: Leister
authors.forename: Jaime
authors.initials: J
authors.lastname: Burns
authors.forename: Daryl
authors.initials: D
authors.lastname: Sonnichsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001372:Aza Compounds / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010919:Placebos; D011804:Quinolines / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D010919:Placebos; D011804:Quinolines; C487932:neratinib; D007654:Ketoconazole; D000077266:Moxifloxacin