Lack of pharmacokinetic interaction between nebivolol and spironolactone

Abstract

Background To detect interaction between nebivolol (N), a unique cardioselective β‐blocker shown to possess vascular endothelial nitric oxide releasing capabilities, and spironolactone by comparing pharmacokinetic (PK) parameters for spironolactone (S) and metabolites, canrenone (C) and 7α‐thiomethyl spirolactone (TMS), in healthy subjects. This potassium‐sparing diuretic (S) is used with β‐blockers to treat CHF. Previously, S showed no effect on the PK of N. Methods Thirty‐six healthy subjects were enrolled, without regard to CYP2D6 genotype, in this open‐label, randomized, one period study. Subjects received once‐daily oral S (25 mg) on Days 1–10 and oral S (25 mg) plus N (10 mg) once‐daily on Days 11–20. Blood samples were collected on Days 10 and 20 and prior to dosing on Days 8, 9, 18, and 19. Plasma concentrations of S, C and TMS were measured by LC/MS. Pharmacokinetic parameter estimates for S, C and TMS were compared by statistical analyses using 90% confidence intervals (CIs). Results All treatments were well tolerated. (see Table) Conclusion Co‐administration of N (10 mg) with S (25 mg) results in no clinically significant changes in the PK profile of S, C or TMS. Clinical Pharmacology & Therapeutics (2005) 77, P46–P46; doi: Cmax AUCT Analyte Ratio 90% CI Ratio 90% CI S1.060.95–1.190.950.90–1.02C1.041.00–1.091.051.03–1.08TMS1.191.10–1.291.141.07–1.20

Nebivolol: Pharmacologic Profile of an Ultraselective, Vasodilatory β1‐Blocker

“…These results are particularly important because β‐blockers are often used with diuretics and ACE inhibitors for the treatment of CHD and HF. In addition, coadministration of nebivolol with spironolactone and digoxin, which are also commonly used with β‐blockers to treat severe HF, caused no clinically significant pharmacokinetic interactions 61 , 62 . Because warfarin is known to have numerous drug‐drug interactions of clinical significance, the effect of the coadministration of nebivolol on the pharmacokinetic and anticoagulant actions of warfarin was studied in 12 healthy volunteers 63 .…”

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.…”