A pharmacokinetic drug interaction study between nebivolol and paroxetine in healthy volunteers

What is known and objective 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. Methods 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. Results and discussion Pretreatment with paroxetine increased the mean peak plasma concentrations (Cmax) for unchanged nebivolol (1 center dot 78 +/- 1 center dot 17 vs. 4 center dot 24 +/- 1 center dot 67ng/mL) and for its active metabolite (0 center dot 58 +/- 0 center dot 21 vs. 0 center dot 79 +/- 0 center dot 24ng/mL) compared to nebivolol alone. The time (tmax) to reach Cmax was 1 center dot 37 +/- 0 center dot 88 (h) and 3 center dot 11 +/- 1 center dot 76 (h) for the parent compound and its active metabolite after nebivolol administered alone and 3 center dot 96 +/- 1 center dot 76 (h), respectively, 7 center dot 33 +/- 7 center dot 84 (h) after pretreatment with paroxetine. Also, the total areas under the curve (AUC0-) were significantly increased from 17 center dot 26 +/- 43 center dot 06 to 106 center dot 20 +/- 65 center dot 56hng/mL for nebivolol unchanged and 13 center dot 03 +/- 11 center dot 29 to 74 center dot 56 +/- 88 center dot 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. What is new and conclusion After pretreatment with paroxetine, the exposure to nebivolol was increased by 6 center dot 1-fold for the parent drug and 5 center dot 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.