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

Abstract

-PURPOSE:To investigate whether fluvoxamine coadministration can influence the pharmacokinetic properties of nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) and to assess the consequences of this potential pharmacokinetic interaction upon nebivolol pharmacodynamics. METHODS:This open-label, non-randomized, sequential clinical trial consisted of two periods: Period 1 (Reference), during which each volunteer received a single dose of 5 mg nebivolol and Period 2 (Test), when a combination of 5 mg nebivolol and 100 mg fluvoxamine was given to all subjects, after a 6-days pretreatment regimen with fluvoxamine (50-100 mg/day). Non-compartmental analysis was used to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The pharmacodynamic parameters (blood pressure and heart rate) were assessed at rest after each nebivolol intake, during both study periods. RESULTS: Fluvoxamine pretreatment increased C max and AUC 0-∞ of nebivolol (C max : 1.67 ± 0.690 vs 2.20 ± 0.970 ng/mL; AUC 0-∞ : 12.1 ± 11.0 vs 19.3 ± 19.5 ng*h/mL ) and of its active metabolite (C max : 0.680 ± 0.220 vs 0.960 ± 0.290 ng/mL; AUC 0-∞ : 17.6 ±20.1 vs 25.5 ± 29.9 ng*h/mL). Apart from C max , AUC 0-t and AUC 0-∞ , the other pharmacokinetic parameters (t max , k el and t ½ ) were not significantly different between study periods. As for the pharmacodynamic analysis, decreases in blood pressure and heart rate after nebivolol administration were similar with and without fluvoxamine concomitant intake. CONCLUSIONS: Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite in healthy volunteers. This did not influence the blood pressure and heart-rate lowering effects of the beta-blocker administered as single-dose. However, more detail studies involving actual patients are required to further investigate the clinical relevance of this drug interaction.

Co‐Prescription of Strong CYP1A2 Inhibitors and the Risk of Tizanidine‐Associated Hypotension: A Retrospective Cohort Study

“…For example, triamterene, verapamil, betaxolol, carvedilol, and propranol have complex metabolism partially involving CYP1A2, 15 and fluvoxamine increases the AUC of the B-blocker nebivolol from 12.1 ± 11.0 to 19.3 ± 19.5 ng hour/mL. 16 The study has some limitations. First, it reflects hypotensive events experienced at the hospital.…”

“…Although no antihypertensive agents appear in the list of sensitive to moderate sensitive CYP1A2 substrates, it is possible that fluvoxamine or ciprofloxacin could have interacted with some antihypertensive agents. For example, triamterene, verapamil, betaxolol, carvedilol, and propranol have complex metabolism partially involving CYP1A2, and fluvoxamine increases the AUC of the B‐blocker nebivolol from 12.1 ± 11.0 to 19.3 ± 19.5 ng hour/mL …”

Influence of Fluvoxamine on Carvedilol’s Pharmacokinetics in Rats

“…Fluvoxamine is an antidepressant agent which belongs to the selective serotonin reuptake inhibitors, SSRIs [11,14] and is used in patients with depression or other psychiatric diseases [13,20]. It has a good absorption (more than 90%) and a low plasma protein binding (77%), being metabolized in the liver and excreted in urine [9,10,16].…”