title: Ipragliflozin does not prolong QTc interval in healthy male and female subjects: a phase I study.
abstract: BACKGROUND
  Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval.
  
  
  OBJECTIVE
  The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects.
  
  
  METHODS
  This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms.
  
  
  RESULTS
  A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms).
  
  
  CONCLUSIONS
  No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.
authors.affiliation: Astellas Pharma Global Development, Inc, Northbrook, IL, USA. wenhui.zhang@astellas.com
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.forename: Ronald
authors.initials: R
authors.lastname: Smulders
authors.forename: Anura
authors.initials: A
authors.lastname: Abeyratne
authors.forename: Albert
authors.initials: A
authors.lastname: Dietz
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kadokura
authors.forename: James
authors.initials: J
authors.lastname: Keirns
mesh_terms: D000328:Adult; D001741:Black or African American; D001372:Aza Compounds / Q000008:administration & dosage* / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D005960:Glucosides / Q000008:administration & dosage* / Q000494:pharmacology*; D064368:Healthy Volunteers; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage* / Q000494:pharmacology*; D044465:White People; D055815:Young Adult
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; D005960:Glucosides; D011804:Quinolines; D013876:Thiophenes; C572941:ipragliflozin; D000077266:Moxifloxacin
keywords: Phase 1; QTc interval prolongation; SGLT2 inhibition; cardiac repolarization; diabetes; ipragliflozin