No effect of concomitant administration of nebivolol and losartan in healthy volunteers genotyped for CYP2D6 status

Abstract

Background Nebivolol (N) has been shown through a number of studies to be a cardioselective β1‐antagonist with vascular endothelial nitric oxide releasing capabilities that exhibits CYP2D6‐mediated polymorphic metabolism. Losartan (L), an ARB, is extensively metabolized by CYP2C9 (a known polymorphic enzyme) and is likely to be used concomitantly. This study examined if co‐administration of N and L alters the pharmacokinetic (PK) characteristics of either agent, or the active metabolite of L, EXP‐3174. Methods This open‐label study was conducted in 24 subjects, genotyped for CYP2D6 status (EM n=20; PM n=4). Using a two‐sequence, two‐treatment design, single doses of 10 mg N (Day 1 or 29), 50 mg L (Day 1 or 29), or their combination (Day 15) were given. Blood samples for PK assessment were taken on Days 1, 15 and 29. Results (see Table) Conclusion There were no clinically meaningful changes observed in the PK of either L or N, confirming that the two agents should be capable of being safely co‐administered. Clinical Pharmacology & Therapeutics (2005) 77, P82–P82; doi: Cmax AUC0‐∞ Parameter Ratio 90% CI Ratio 90% CI EM‐N0.800.68–0.930.890.82–0.97PM‐N0.930.76–1.140.940.68–1.29L0.890.77–1.020.860.81–0.92EXP‐31740.940.86–1.030.980.94–1.02

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

“…A study (n = 24) of the coadministration of single doses of nebivolol 10 mg and losartan 50 mg, an angiotensin II receptor blocker that is extensively metabolized by CYP2C9 (a known polymorphic enzyme), found that neither agent had any effect on the pharmacokinetics of the other drug in either EM or PM subjects 58 . In other studies, no drug interactions affecting the pharmacokinetics of either agent were reported with coadministration of nebivolol and the ACE inhibitor ramipril or the diuretic furosemide 59 , 60 .…”

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.…”

Overview of Pharmacogenetics

“…The FDA has recommended screened designs for CYP2D6-, CYP2C19-, or CYP2C9-mediated drug-drug interaction studies (FDA, 2004a). Several companies have reported results from such studies (Lawrence et al, 2005;Li et al, 2005;Small et al, 2005). Selected clinical trials ( Fig.…”