title: Preladenant, a selective adenosine A₂A receptor antagonist, is not associated with QT/QTc prolongation.
abstract: OBJECTIVE
  Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization.
  
  
  METHODS
  This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5.
  
  
  RESULTS
  The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID.
  
  
  CONCLUSIONS
  At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.
authors.affiliation: Clinical Research, MSD, 20/F Park Place, 1601 Nanjing Road (West), Jing'an District, Shanghai, 200040, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: F
authors.initials: F
authors.lastname: Xuan
authors.forename: W H
authors.initials: WH
authors.lastname: Lin
authors.forename: M D
authors.initials: MD
authors.lastname: Troyer
authors.forename: A
authors.initials: A
authors.lastname: Tendolkar
authors.forename: D L
authors.initials: DL
authors.lastname: Cutler
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D001372:Aza Compounds / Q000008:administration & dosage / Q000009:adverse effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011743:Pyrimidines; D011804:Quinolines; D014230:Triazoles; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine; D000077266:Moxifloxacin