Lack of effect of reboxetine on cardiac repolarization

Objective: The effect of reboxetine on electrocardiographic parameters, par ticularly the QTc interval, was assessed in 20 healthy subjects (15 male; 5 female). Methods: In a 5-way crossover stud; 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 (EC Gs) were obtained during one dosing interval of days 1, 4, and 7. Additiona l ECGs were recorded immediately after an exercise paradigm, so that the RR versus QT relationship might be used in calculating QTc. Plasma concentrat ions 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 do se-corrected area under the concentration-time curve from time zero to 12 h ours 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 greater than or equal to8 mg reboxetine daily. No statistically significant prolongation of QTc (Frid ericia correction) occurred after any of the treatments. No relationships b etween Delta QTc and plasma concentrations of reboxetine enantiomers were a pparent. Similar results were obtained with Bazett's correction and two lin ear corrections that relied on exercise data generated before drug administ ration. Conclusions: Reboxetine, at systemic exposures approximately twice the reco mmended dose, did not significantly affect cardiac repolarization in health y subjects. Use of QT versus RR relationship in the drug-free state to corr ect QT for heart rate in the drug-treated state may provide an acceptable a lternative to classic correction equations.