title: Lack of effect of reboxetine on cardiac repolarization.
abstract: OBJECTIVE
  The effect of reboxetine on electrocardiographic parameters, particularly the QTc interval, was assessed in 20 healthy subjects (15 male, 5 female).
  
  
  METHODS
  In a 5-way crossover study, subjects received placebo, 2 mg, 4 mg, or 6 mg reboxetine, or 6 mg reboxetine and 200 mg ketoconazole twice daily for 7 days. Plasma samples, vital signs, and 12-lead electrocardiograms (ECGs) were obtained during one dosing interval of days 1, 4, and 7. Additional ECGs were recorded immediately after an exercise paradigm, so that the RR versus QT relationship might be used in calculating QTc. Plasma concentrations of R,R (-)reboxetine and the more active S,S (+)reboxetine were measured by HPLC-dual mass spectrometry.
  
  
  RESULTS
  No statistically significant differences among treatments in mean dose-corrected pharmacokinetic parameters were observed, except that the dose-corrected area under the concentration-time curve from time zero to 12 hours and the peak plasma concentration were significantly increased on days 4 and 7 in the presence of ketoconazole. As expected, heart rate increased from baseline (approximately 8-11 beats/min) at > or =8 mg reboxetine daily. No statistically significant prolongation of QTc (Fridericia correction) occurred after any of the treatments. No relationships between DeltaQTc and plasma concentrations of reboxetine enantiomers were apparent. Similar results were obtained with Bazett's correction and two linear corrections that relied on exercise data generated before drug administration.
  
  
  CONCLUSIONS
  Reboxetine, at systemic exposures approximately twice the recommended dose, did not significantly affect cardiac repolarization in healthy subjects. Use of QT versus RR relationship in the drug-free state to correct QT for heart rate in the drug-treated state may provide an acceptable alternative to classic correction equations.
authors.affiliation: Clinical Pharmacology Unit, Pharmacia & Upjohn, Inc, Kalamazoo, MI 49007, USA. joseph.c.fleishaker@pharmacia.com
authors.forename: J C
authors.initials: JC
authors.lastname: Fleishaker
authors.forename: S F
authors.initials: SF
authors.lastname: Francom
authors.forename: B D
authors.initials: BD
authors.lastname: Herman
authors.forename: D W
authors.initials: DW
authors.lastname: Knuth
authors.forename: N E
authors.initials: NE
authors.lastname: Azie
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077593:Reboxetine; D013237:Stereoisomerism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000935:Antifungal Agents; D009025:Morpholines; D000077593:Reboxetine; D007654:Ketoconazole