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

Abstract

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.

Investigation of a Potential Pharmacokinetic Interaction Between Nebivolol and Fluvoxamine in Healthy Volunteers

“…On the other hand, pretreatment with duloxetine, a moderate CYP2D6 enzymatic inhibitor, had an impact on nebivolol pharmacokinetics, similar with the one attributed to fluvoxamine in this study. More precisely, in a clinical study that included healthy volunteers, duloxetine was responsible for a 1.19-fold and 1.42-fold increase in the AUC 0-∞ values of nebivolol and its hydroxylated active metabolite (30), which suggests a similar inhibition potency of isoenzyme CYP2D6 for duloxetine and fluvoxamine. After evaluating the magnitude of all the aforementioned metabolism-mediated pharmacokinetic interactions involving nebivolol and antidepressants, fluvoxamine had a much smaller influence upon nebivolol pharmacokinetics compared to other antidepressants like bupropion, paroxetine or fluoxetine.…”

“…Several clinical trials investigated not only whether a drug interaction does exist between enzymatic inhibitors like cimetidine, duloxetine, paroxetine or bupropion and nebivolol, but also whether clinical consequences are associated with these potential drug interactions. Although it was revealed that the aforementioned drugs determined an increased exposure to nebivolol, these drug combinations did not lead to greater reductions of the pharmacodynamic parameters (BP and HR) measured at rest or during exercise (22,23,29,30). Additionally, no published case reports that describe side effects induced by nebivolol when coadministered with fluvoxamine were found in the medical literature.…”

“…We used the means and standard deviations from articles comparing the same 5 mg dose of nebivolol and nebivolol with another inhibitor -paroxetine (22) and cimetidine (23), and we simulated all predictions for a correlation coefficient between the two periods (0.01 -0.99) and 0.5. We obtained a range of predictions between 3 to 19 subjects, and we finally chose a target sample size of 20.…”

“…In comparison to other antidepressants, also known as CYP2D6 inhibitors, the present research revealed that the effect of fluvoxamine on the pharmacokinetics of nebivolol was smaller. Potent inhibitors of the same metabolic pathway, like fluoxetine (12), paroxetine (22) and bupropion (29) had a marked influence upon nebivolol pharmacokinetics and were responsible for an approximately 6-fold to 7-fold increase in AUC 0-∞ . The association of the beta-blocker with bupropion and paroxetine also revealed a 4-fold and 5.7-fold increased exposure to 4-OH-nebivolol, the active hydroxylated metabolite (22,29).…”

“…Potent inhibitors of the same metabolic pathway, like fluoxetine (12), paroxetine (22) and bupropion (29) had a marked influence upon nebivolol pharmacokinetics and were responsible for an approximately 6-fold to 7-fold increase in AUC 0-∞ . The association of the beta-blocker with bupropion and paroxetine also revealed a 4-fold and 5.7-fold increased exposure to 4-OH-nebivolol, the active hydroxylated metabolite (22,29). On the other hand, pretreatment with duloxetine, a moderate CYP2D6 enzymatic inhibitor, had an impact on nebivolol pharmacokinetics, similar with the one attributed to fluvoxamine in this study.…”