Effect of chronic administration of fluoxetine on the pharmacokinetics of nebivolol

Abstract

Background Nebivolol (N) is considered a unique racemic cardio‐selective β1‐antagonist with vascular endothelial nitric oxide modulating capabilities that undergoes extensive metabolism to active moieties via the CYP2D6 enzymatic pathway. Fluoxetine (F), one of the most studied potent inhibitors and substrates of CYP2D6 enzyme used clinically, was selected to assess the potential interactions with N. Methods Ten CYP2D6 extensive metabolizers (EM) received an oral 10 mg dose of N on Day 1, an oral 20 mg dose of F QD on Days 8 through 27, and 10 mg N plus 20 mg F on Day 28. PK estimates for N were assessed. Results (see Table) Co‐administration of N with F was well tolerated. Conclusions The results confirm N's reliance on the CYP2D6 enzymatic pathway for elimination. The elevated N plasma concentrations seen with the co‐administration of F were considerably lower than the clinically safe and well‐tolerated levels of N alone previously observed in poor metabolizer subjects (AUC∞: 614 ng·hr/mL; Cmax: 9.21 ng/mL). Clinical Pharmacology & Therapeutics (2005) 77, P38–P38; doi: Parameter Day 1 Day 28 Ratio 90% CI AUC∞ (ng hr/mL)13.8792.336.024.57–7.91Cmax (ng/mL)2.335.452.271.83–2.80Tmax (hr)1.302.602.001.58–2.42t1/2 (hr)12.5117.451.401.07–1.72Cl/F (L/hr)787.0142.90.180.014–0.35

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

“…More specifically, the mean peak plasma concentrations ( C max ) of nebivolol (1·78 ± 1·17 vs. 4·24 ± 1·67 ng/mL) and its hydroxylated metabolite (0·58 ± 0·21 vs. 0·79 ± 0·24 ng/mL) were about 2·3, respectively, 1·3 times higher after pretreatment with paroxetine than the levels produced by nebivolol alone. When fluoxetine, another CYP2D6 inhibitor, was co‐administered with nebivolol, this interaction resulted in markedly elevated plasma concentrations of nebivolol that were three times higher than normal . Also, cimetidine was associated with a 21–23% increase in plasma levels of unchanged nebivolol and its metabolites, when in this study, the increase produced by paroxetine was in the range of 36% for the metabolite and 138% for nebivolol unchanged.…”

“…The present study included twenty-three healthy volunteers (16 caucasian males and seven caucasian females) with age of 25Á7 AE 3Á0 years (range: 20-35 years) and with a body mass index (BMI) of 24Á0 AE 3Á0 (range: [19][20][21][22][23][24][25]. All the volunteers completed the study and were included in the per-protocol analysis set.…”

Nebivolol

“…[63][64][65][66][67][68][69][70] However, 3-fold increases in nebivolol peak plasma concentrations and 8-fold increases in area under the curve occur during concomitant administration with fluoxetine, a known CYP2D6 inhibitor, and therefore caution should be exercised when administering nebivolol and any CYP2D6 inhibitor in hypertensive patients. 71 Given the negative chronotropic and inotropic properties and the antihypertensive effects of nebivolol, it is likely that a pharmacodynamic interaction may exist between nebivolol and other agents with similar properties. Therefore, caution should …”