Evaluation of the potential pharmacokinetic/pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers

Objective: This study was performed to assess the tolerability of combined administration of reboxetine, a selective noradrenaline (norepinephrine) reuptake inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor, relative to administration of each drug separately. Design: The following treatments were administered for 8 days according to a randomised, double-blind, placebo-controlled parallel design: (a) oral reboxetine 4mg twice daily, (b) oral fluoxetine 20mg once daily, or (c) oral reboxetine 4mg twice daily and fluoxetine 20mg once daily. Participants: Thirty healthy, nonsmoking volunteers (27 male, three female), aged between 20 and 55 years and within 15% of normal bodyweight were included in the study. Target Parameters: Plasma reboxetine enantiomers were quantified using HPLC-MS-MS. Fluoxetine and norfluoxetine concentrations were determined using high performance liquid chromatography. Pharmacokinetic parameters were compared by unpaired t-test. Clinical laboratory data were analysed as the change from baseline, and adverse events were tabulated by treatment. Vital sign and Digit Symbol Substitution Test (DSST) data were analysed by repeated measures analysis of variance. Results: The adverse event profiles were similar for combined reboxetine and fluoxetine relative to administration of each drug separately. Reboxetine significantly increased mean standing and supine heart rate versus baseline, whereas heart rate was not modified by fluoxetine. No statistically significant treatment effects were seen for DSST scores or oral temperature. The area under the plasma concentration-time curve from 0 to 12 hours for S,S(+) reboxetine was approximately 23% higher with fluoxetine coadministration than with reboxetine alone, but this effect, as well as effects on other pharmacokinetic parameters for either reboxetine enantiomer, was not statistically significant. In addition, no statistically significant effects of reboxetine on fluoxetine or norfluoxetine pharmacokinetics were observed. Conclusion: Combined administration of reboxetine and fluoxetine was well tolerated in healthy volunteers. These results suggest minimal clinical impact when these drugs are administered concomitantly to depressed patients.