title: Repeated supratherapeutic dosing of strontium ranelate over 15 days does not prolong QT(c) interval in healthy volunteers.
abstract: OBJECTIVE
  The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QT(c) studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹ for 15 days) with placebo on the largest time-matched mean QT(c) variation, from baseline to under treatment values, in healthy subjects.
  
  
  METHODS
  Ninety-six healthy male and female subjects (27.7 ± 7.5 years) were included to receive 1 day of placebo followed by 15 days of supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹), in a 4 month, randomized, placebo (16 days) and positive-controlled (single dose of moxifloxacin 400 mg preceded by 15 days of placebo), double-blind, double dummy, crossover design. Measurement of QT interval was performed automatically on the ECGs with subsequent manual onscreen over-reading by cardiologists using electronic callipers.
  
  
  RESULTS
  The largest time-matched difference in QT(c) I (individual QT correction for heart rate) between moxifloxacin 400 mg and placebo was observed at 2 h post dose (mean [95% CI] 10.62 [7.90, 13.35] ms). For strontium ranelate (4 g day⁻¹) the largest time-matched difference in QT(c) I compared with placebo was observed at 1 h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). No subject had a QT(c) greater than 480 ms during the study. Both moxifloxacin and strontium ranelate were well tolerated in healthy subjects.
  
  
  CONCLUSIONS
  The findings of this study demonstrate that the administration of supratherapeutic repeated oral doses of strontium ranelate (4 g day⁻¹ for 15 days) does not lead to a prolongation of the QT/QT(c) interval above the threshold of regulatory concern.
authors.affiliation: Richmond Pharmacology Ltd, St George's University of London, Cranmer Terrace, London, United Kingdom. j.taubel@richmondpharmacology.com
authors.forename: Jorg
authors.initials: J
authors.lastname: Taubel
authors.forename: Asif
authors.initials: A
authors.lastname: Naseem
authors.forename: Duolao
authors.initials: D
authors.lastname: Wang
authors.forename: Radivoj
authors.initials: R
authors.lastname: Arezina
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lorch
authors.forename: A John
authors.initials: AJ
authors.lastname: Camm
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage; D001372:Aza Compounds / Q000008:administration & dosage; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008131:London; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D000077266:Moxifloxacin; D017711:Nonlinear Dynamics; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061214:Patient Safety; D011237:Predictive Value of Tests; D011804:Quinolines / Q000008:administration & dosage; D018570:Risk Assessment; D012307:Risk Factors; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D050071:Bone Density Conservation Agents; D024841:Fluoroquinolones; D009942:Organometallic Compounds; D011804:Quinolines; D013876:Thiophenes; C081587:strontium ranelate; D000077266:Moxifloxacin