Abstract
Nebivolol is a highly selective beta-blocker with additional vasodilator properties, widely used in the clinical practice for the treatment of hypertension and heart failure. Paroxetine is a second-generation antidepressant and a potent inhibitor of CYP2D6, the same isoenzyme involved in the metabolism of nebivolol. The objective of this study was to investigate the effect of multiple-dose paroxetine intake on the pharmacokinetics of nebivolol in healthy volunteers and its potential consequences upon nebivolol pharmacodynamics. The study included 23 healthy subjects and was designed as an open-label, single-centre, non-randomized, two-period clinical trial. During period 1 (reference), each volunteer received a single dose of 5mg nebivolol, whereas during period 2 (test), each volunteer received a single dose of 5mg nebivolol and 20mg paroxetine, after a pretreatment regimen with paroxetine (20-40mg/day for 6days). The pharmacokinetic parameters of nebivolol and its active metabolite were analysed by non-compartmental modelling. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest, after each nebivolol intake. Pretreatment with paroxetine increased the mean peak plasma concentrations (Cmax ) for unchanged nebivolol (1·78±1·17 vs. 4·24±1·67ng/mL) and for its active metabolite (0·58±0·21 vs. 0·79±0·24ng/mL) compared to nebivolol alone. The time (tmax ) to reach Cmax was 1·37±0·88 (h) and 3·11±1·76 (h) for the parent compound and its active metabolite after nebivolol administered alone and 3·96±1·76 (h), respectively, 7·33±7·84 (h) after pretreatment with paroxetine. Also, the total areas under the curve (AUC0-∞ ) were significantly increased from 17·26±43·06 to 106·20±65·56hng/mL for nebivolol unchanged and 13·03±11·29 to 74·56±88·77hng/mL for its hydroxylated metabolite, before and after paroxetine intake. All the pharmacokinetic parameters presented statistically significant differences when paroxetine was administered with nebivolol. Nonetheless, statistical analysis did not show a significant difference between the vital signs measured during the two periods. After pretreatment with paroxetine, the exposure to nebivolol was increased by 6·1-fold for the parent drug and 5·7-fold for the hydroxylated active metabolite. Paroxetine influenced nebivolol pharmacokinetics in healthy volunteers, but it did not have a significant effect on nebivolol pharmacodynamic parameters measured at rest, although the clinical relevance of this drug interaction needs further investigation.
Published Version
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