Deferasirox does not induce QT/QTc-prolongation in healthy subjects.
The International Conference on Harmonization (ICH) E14 guidance recommends that almost all drugs should undergo careful clinical testing in a thorough QT/QTc study. Deferasirox (Exjade, ICL670) is a once-daily oral iron chelator, developed for the treatment of blood transfusion-related iron overload.


OBJECTIVE
This study was designed to investigate the effect of deferasirox on the QT/QTc interval.


METHODS
A randomized, single-dose, placebo- and positive-controlled, parallel-group study was conducted in a total of 182 healthy subjects. Study participants were randomized to four treatments arms: deferasirox 20 mg/kg (n = 46), deferasirox 40 mg/kg (n = 46), placebo (n = 46) or moxifloxacin 400 mg (n = 44). Moxifloxacin tablets were taken in an open-label fashion, while the subjects and investigator staff remained blinded for the other treatments. Electrocardiograms, obtained at various time points during a 24-h period, were evaluated centrally in a blinded fashion. The primary endpoint was the average change from baseline in QT/QTc over the 24-h period following intake of study medication. It was prospectively defined that deferasirox will be considered devoid of inducing QT/QTc-prolongation if the upper bound of the 95% 2-sided confidence interval (CI) for the difference to placebo is below 8 milliseconds (i.e., being noninferior to placebo).


RESULTS
Deferasirox 20 and 40 mg/kg were noninferior to placebo with respect to the average change from baseline in QT/QTc, as indicated by 95% CIs for the mean treatment difference (deferasirox 20 or 40 mg/kg minus placebo), which were entirely below 8 milliseconds. The lower limit of the 95% 2-sided CI for the difference between moxifloxacin and placebo was greater than 0 milliseconds, demonstrating the sensitivity of the study. Deferasirox C(max) and AUC following intake of deferasirox 40 mg/kg was higher by factor 1.6 and 2.3, respectively, than observed at a steady state in beta-thalassemia patients treated for 6 months with deferasirox 30 mg/kg, the recommended maximum dose.


CONCLUSIONS
This study demonstrates that deferasirox does not prolong the QT/QTc interval at both therapeutic and supratherapeutic plasma concentrations. It is, therefore, not expected that deferasirox has a negative effect on cardiac repolarization in patients under treatment with this medication.
Sechaud
R
R
Novartis Institutes for BioMedical Research, Translational Sciences, Basel, Switzerland. romain.sechaud@novartis.com
Dumortier
T
T
Balez
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001372:Aza Compounds / Q000633:toxicity; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000077588:Deferasirox; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000633:toxicity; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D055815:Young Adult
D001372:Aza Compounds; D001565:Benzoates; D024841:Fluoroquinolones; D007502:Iron Chelating Agents; D011804:Quinolines; D014230:Triazoles; D000077266:Moxifloxacin; D000077588:Deferasirox