title: Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies.
abstract: OBJECTIVE
  Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial.
  
  
  METHODS
  Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals.
  
  
  RESULTS
  Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship.
  
  
  CONCLUSIONS
  Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA 02139, USA.
authors.forename: Daryl
authors.initials: D
authors.lastname: Sonnichsen
authors.forename: David J
authors.initials: DJ
authors.lastname: Dorer
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Dale
authors.initials: D
authors.lastname: Bixby
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mauro
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Litwin
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects*; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib