title: Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women.
abstract: OBJECTIVE
  Retosiban is a small molecule oxytocin receptor antagonist that is under evaluation in clinical studies for treatment of spontaneous preterm labor. A Thorough QT/QTc study was conducted to evaluate the effect of retosiban on cardiac repolarization according to International Conference on Harmonization E14 guidance. This was a randomized, placebo- and positive-controlled, single-dose, crossover study of healthy men and women.
  
  
  METHODS
  All study participants received a 100 mg dose of retosiban (therapeutic target exposure), a 800 mg dose of retosiban (supratherapeutic target exposure), a 400 mg dose of moxifloxacin (positive control), and placebo with an appropriate washout. Holter monitoring data at baseline (predose) and at 13 subsequent time points during the next 24 hours were extracted and manually read by a central ECG reader who was blinded to the treatment assignment and corrected for heart rate by using the Fridericia formula (QTcF). A linear exposure-QTc response model was developed: ΔΔQTcF=RI+Cp,R⋅RS+MI+Cp,M⋅MS, where RI and MI are intercept terms for retosiban and moxifloxacin, respectively, RS and MS are slope terms for retosiban and moxifloxacin, respectively, and Cp,R and Cp,M are plasma concentrations for retosiban and moxifloxacin, respectively.
  
  
  RESULTS
  A total of 52 healthy men (n = 27) and women (n = 25), with a mean age of 32 years, were enrolled in the study, and 43 (83%) completed all treatment periods and assessments. Mean placebo-corrected change from baseline QT (ΔΔQTcF) for the 2 retosiban dose groups revealed statistically significant decreases in ΔΔQTcF between 2 and 3 hours after administration, reaching a value of -2.5 msec for both retosiban dose groups. The 400 mg moxifloxacin group had a statistically significant increase in the ΔΔQTcF value at 0.75 hours after administration, reaching a maximal increase of 11.10 msec at 4 hours after administration. Results of the exposure-QTc response modeling revealed that there was no significant effect of retosiban on the ΔΔQTcF at therapeutic exposures. For the supratherapeutic exposure of retosiban, there was a slight negative effect, with a mean decrease of -3.05 msec. The moxifloxacin arm had a mean increase in ΔΔQTcF of 10.7 msec.
  
  
  CONCLUSIONS
  At therapeutic and supratherapeutic exposures, retosiban had no significant effect on cardiac repolarization, as estimated by the ΔΔQTcF. However, both doses of retosiban had a minor shortening effect. This is not considered to be clinically significant. CLINICALTRIALS.
  NCT01702376.
authors.affiliation: Clinical Pharmacology Science & Study Operations, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Brendt
authors.initials: B
authors.lastname: Stier
authors.affiliation: Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Fossler
authors.affiliation: Clinical Statistics, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Clinical Pharmacology, GlaxoSmithKline, King of Prussia, Pennsylvania. Electronic address: stephen.caltabiano@gsk.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Caltabiano
mesh_terms: D000328:Adult; D001372:Aza Compounds / Q000008:administration & dosage; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D015716:Electrocardiography, Ambulatory; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D064368:Healthy Volunteers; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; C522194:GSK221149A; D010879:Piperazines; D018045:Receptors, Oxytocin; D000077266:Moxifloxacin
keywords: ECG; cardiac repolarization; oxytocin antagonist; preterm labor; retosiban