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NEW DRUG DEVELOPMENTS

Nebivolol: A Third-Generation ß-Adrenergic Blocker

Assistant Professor of Pharmacy, School of Pharmacy, Wingate University, Wingate, NC

Donald S Nuzum, PharmD

Assistant Professor of Pharmacy, School of Pharmacy, Wingate University

Jamie L Jolly, PharmD CDE

at time of writing, Assistant Professor of Pharmacy, School of Pharmacy, Wingate University; now, Medical Liaison, Daiichi Sankyo Inc., Parsippany, NJ

Reprints: Dr. Veverka, School of Pharmacy, Wingate University, 316 N. Main St., Wingate, NC 28174-0157, fax 704/233-8332, aveverka{at}wingate.edu

	Abstract

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OBJECTIVE: To describe the pharmacologic and pharmacokinetic properties of a new ß-adrenergic blocker, nebivolol, and review the literature evaluating its efficacy in the treatment of hypertension and heart failure.

DATA SOURCES: Articles were identified through searches of MEDLINE (1996-May 2006) and International Pharmaceutical Abstracts (1970-May 2006), using the key word nebivolol. Additional references were selected from the bibliographies of the articles cited. Searches were not limited by language, time, or human subject.

STUDY SELECTION AND DATA EXTRACTION: Preclinical studies evaluating the pharmacologic and pharmacokinetic properties of nebivolol in humans were selected for review. Randomized, controlled, blinded clinical trials assessing the efficacy of nebivolol for the treatment of hypertension and heart failure were also included.

DATA SYNTHESIS: Preclinical data have established nebivolol as a third-generation ß-adrenergic blocker, as it possesses vasodilatory properties that contribute to its hemodynamic effects beyond those achieved at ß-adrenergic receptors. Short-term, randomized, controlled clinical trials have shown nebivolol to be as effective as other antihypertensive therapies at lowering blood pressure. One long-term trial showed a significant reduction in death and hospital admissions for cardiovascular causes when nebivolol was compared with placebo in patients with heart failure (31.1% vs 65.3%; HR 0.86; 95% CI 0.74 to 0.99).

CONCLUSIONS: Nebivolol is a novel ß-adrenergic blocker that possesses unique pharmacologic properties, compared with other agents in its class. Nebivolol appears to be as effective as other antihypertensive agents at lowering blood pressure and possesses benefits for patients with heart failure. Additional studies are needed to address the long-term benefits of nebivolol for hypertension, to compare nebivolol with other ß-adrenergic blockers for heart failure, and to investigate the clinical relevance of nitric oxide-mediated vasodilation.

Key Words: ß-adrenergic blockers, heart failure, hypertension, nebivolol, nitric oxide

Published Online, July 5, 2006. www.theannals.com, DOI 10.1345/aph.1G708

This article provides an overview of the pharmacologic and pharmacokinetic properties of nebivolol and reviews clinical data establishing its efficacy for the treatment of essential hypertension and heart failure.

	Data Sources and Selection

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A primary literature search was conducted via MEDLINE (1996-May 2006) and International Pharmaceutical Abstracts (1970-May 2006) using the search term nebivolol. Searches were not limited by language, time restrictions, or human subjects. Additional articles were selected from the bibliographies of the cited references. Preclinical studies evaluating the pharmacokinetic and pharmacologic properties of nebivolol in humans were selected for review. Clinical trials that evaluated nebivolol in patients with essential hypertension or heart failure were included if they met the following criteria: randomized, blinded (single or double), placebo-controlled or compared with an established therapy for a given condition, and treatment for at least 8 weeks. Only heart failure trials in which patients were treated with adequate baseline therapy according to current standards of care were included.

	Pharmacology

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The cardiovascular endothelium regulates vascular tone and maintains homeostasis by releasing a variety of vasoactive compounds. Nitric oxide is a major endotheliumderived vasoactive compound that produces vasodilation by enhancing cyclic guanosine monophosphate and also inhibits platelet aggregation and smooth-muscle cell proliferation.^1,2 Cardiovascular diseases such as hypertension, atherosclerosis, stroke, and heart failure can place stress on the protective endothelium and disrupt the function of nitric oxide on the vasculature. Nitric oxide deficiency can result from a decrease in nitric oxide synthesis from the amino acid L-arginine, enhanced nitric oxide inactivation, or impaired bioavailability of bioactive nitric oxide. This impaired nitric oxide bioavailability can lead to decreased arterial elasticity and increased peripheral vascular resistance.^3-5

Nebivolol is a ß₁-selective adrenergic blocker that has additional vasodilating activity mediated by the L-arginine-nitric oxide pathway, a unique mechanism compared with currently marketed agents in this drug class (Figure 1).^2,6 In animal studies, nebivolol produced arterial vasodilation that was antagonized by coinfusion of nitric oxide synthase inhibitors such as N^G-monomethyl-L-arginine (L-NMMA).^7-10 Additionally, increases in nitric oxide bioavailability caused by administration of nebivolol may be due to inhibition of reactive oxygen species, which inactivate nitric oxide, or agonist activity of the drug at endothelial ß₃-adrenoreceptors.^11-13 The presence of a ß₃-adrenoreceptor in human myocardium has been identified, with subsequent evidence suggesting that agonist activity at this receptor induces nitric oxide production.¹⁴ Trials assessing the pharmacologic properties of nebivolol in healthy or diseased humans have confirmed its ability to stimulate the L-arginine-nitric oxide pathway and decrease oxidative stress.^15-17

View larger version (14K): [in this window] [in a new window]   Figure 1. The effect of nebivolol on vascular relaxation via the L-arginine-nitric oxide pathway. cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; NOS = nitric oxide synthase. Adapted.2,6

A second study evaluated the effects of nebivolol compared with atenolol in phenylephrine-preconstricted dorsal veins of 11 healthy men.¹⁸ Only nebivolol caused venodilation with phenylephrine preconstriction, an effect that was antagonized by L-NMMA. The effects of nebivolol on prostaglandin F₂-preconstricted veins were also assessed to determine whether nebivolol has any -adrenergic antagonist activity. The vasodilation induced by nebivolol with prostaglandin preconstriction was similar to that observed with phenylephrine preconstriction, supporting the theory that nebivolol vasodilation is mediated by nitric oxide with no antagonist effects at -adrenergic receptors.

Nebivolol is a racemic mixture of L-nebivolol (RSSS) and D-nebivolol (SRRR), the 2 enantiomers being present in equal proportions, as both are necessary for the drug to have maximum effect. The D-isomer provides the ß₁-receptor blocking properties, having an affinity for ß₁-receptors that is greater than 100-fold higher than that of the L-isomer. Both the D- and L-isomers facilitate nitric oxide release to induce a vasodilatory effect.^15,17,19,20 Nebivolol has a higher degree of ß₁-selectivity than any other ß-blocker currently used in clinical practice, demonstrating a 321-fold higher affinity for human cardiac ß₁-versus ß₂-receptors.²¹ Nebivolol is 3-10 times more ß₁-selective than are bisoprolol and metoprolol and has no intrinsic sympathomimetic activity or -blocking properties.^15,21,22 The rank order of ß₁-selectivity in human myocardium is nebivolol > bisoprolol > metoprolol > carvedilol propranolol = bucindolol.^21,22

Van Bortel et al.²³ evaluated the ß₁-blocking potency of nebivolol compared with that of atenolol, as well as nebivolol's effects after repeated dosing. After 7 days of therapy, the effects of nebivolol 5 mg on exercise-induced tachycardia were similar to those of atenolol 25 mg, suggesting that nebivolol is 5 times more potent than atenolol in its ß₁-antagonist effects. The ß₁-blocking effects of nebivolol were significantly greater after 7 days of therapy than after a single dose, suggesting accumulation of nebivolol or active metabolites. The blood pressure-lowering effects of nebivolol 5 mg, administered once daily, were similar to those of atenolol 100 mg administered once daily. This suggests that nebivolol has an ancillary property that lowers blood pressure and results in potency that is 20 times higher than that of atenolol. When investigated, -blockade was deemed not to be the reason for nebivolol's hemodynamic properties. The researchers concluded that nebivolol 5 mg would have blood pressure lowering effects equal to those of atenolol 100 mg but, when evaluating heart rate, would potentially have less effect on exercise capacity due to a difference in ß₁-blockade potency.

	Pharmacokinetics and Pharmacodynamics

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Nebivolol is a highly lipophilic drug that is rapidly absorbed following oral administration, reaching peak plasma concentrations in 0.5-2 hours. Absorption is not affected by food or age.²⁴ Nebivolol undergoes extensive first-pass hepatic metabolism and has an oral bioavailability ranging from 12% to 96%, depending on whether the patient is an extensive or poor metabolizer. Nebivolol is a substrate of CYP3A4 but also undergoes oxidation, glucuronidation, hydroxylation, and N-dealkylation to active metabolites. Differences in nebivolol metabolism appear to be due to genetic polymorphisms in hydroxylation, with plasma half-lives of approximately 10 and 30 hours in extensive and poor metabolizers, respectively.^24-27 Since less than 1% of the drug is excreted unchanged in the urine, dosage adjustments in patients with renal failure are unnecessary.²⁶ The volume of distribution of nebivolol is approximately 10 L/kg and is unaffected by obesity, despite being a highly lipophilic agent.²⁵ In plasma, both SRRR- and RSSS-nebivolol are highly protein bound, predominantly to albumin.²⁸

	Clinical Studies

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HYPERTENSION
Early studies assessing the efficacy of nebivolol for the treatment of hypertension were placebo-controlled (Table 1). A randomized, double-blind, placebo-controlled trial was conducted to evaluate the effects of nebivolol in patients with essential hypertension and assess the impact of treatment on their quality of life.²⁹ After a 4 week placebo run-in period, patients were randomized into 3 groups: group 1 (n = 40) received nebivolol 5 mg for 4 weeks, followed by placebo for 4 weeks; group 2 (n = 40) received placebo for 4 weeks, followed by nebivolol 5 mg for 4 weeks; and group 3 (n = 34) received nebivolol 5 mg for 8 weeks. Compared with placebo, 4 weeks of nebivolol treatment (groups 1 and 2) significantly decreased blood pressure in supine (mean decrease 11/8 mm Hg) and standing (mean decrease 16/10 mm Hg) positions as well as heart rate (supine: mean decrease of 12 beats/min; p < 0.01; standing: mean decrease of 16 beats/min; p < 0.001). Quality of life was evaluated in 79 patients using the Inventory of Subjective Health. Ratings did not differ between treatment groups, indicating that quality of life was not impaired with nebivolol therapy. When comparing 4 and 8 weeks of nebivolol treatment, differences in supine and standing blood pressure and heart rate at the end of the treatment periods did not differ significantly between groups.

The effects of nebivolol 5 mg were compared with those of atenolol 50 mg and placebo in a randomized, double-blind, parallel-group study of patients with essential hypertension.³⁰ After a 4 week run-in period with placebo, patients were randomized to 4 weeks of treatment with nebivolol or atenolol. After 2 weeks and throughout the treatment period, both drugs significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared with placebo. With active treatment, heart rate decreased significantly at 4 weeks compared with placebo (p < 0.001 for both drugs). A subsequent study established similar blood pressure-lowering effects with these agents.³¹ Patients were treated with the study drug over a 12 week period with the option of adding hydrochlorothiazide 12.5 mg after 8 weeks of monotherapy if blood pressure was 140/90 mm Hg or higher or if DBP reduction was less than 10 mm Hg. Reductions in sitting and standing SBP and DBP comparable to those in the Van Nueten study³⁰ were observed after 2 weeks of treatment.³¹ Further reductions in blood pressure for the remainder of the trial were small but still similar between groups. Heart rates were significantly decreased in both treatment groups compared with baseline; however, atenolol therapy resulted in greater reductions in heart rate that were significantly different from those seen with nebivolol.

Nebivolol 5 mg was compared with bisoprolol 5 mg in a multicenter, single-blind, randomized, parallel-group trial.³² The study assessed the effect of drug therapy in patients with mild-to-moderate essential hypertension and evaluated the clinical relevance of the nitric oxide-mediated vasodilatory effect of nebivolol on clinical endpoints. The primary endpoint was the percentage of responders achieving DBP normalization (90 mm Hg) or a DBP reduction of at least 10 mm Hg. After 12 weeks of treatment, there was no statistically significant difference in the primary endpoint between groups (nebivolol -15.7 ± 6.4 mm Hg vs bisoprolol -16.0 ± 6.8 mm Hg; p = 0.8230). Similar reductions in SBP and heart rate were observed in both groups. The clinical relevance of the vasodilatory effects of nebivolol on clinical endpoints was not adequately assessed in this trial. Although it was an objective listed by the authors, there were no primary or secondary endpoints designed to address this question, beyond those assessing blood pressure-lowering effects.

Two studies have compared the antihypertensive effect of nebivolol 5 mg once daily with that of an angiotensinconverting enzyme (ACE) inhibitor. Van Nueten et al.³³ used enalapril 10 mg once daily as the comparator agent in a randomized, double-blind trial. The predeclared index measurement of DBP at trough level was significantly lower with nebivolol at the end of the trial, and there was a higher number of responders, defined as a trough DBP while sitting of 90 mm Hg or less or a decrease of at least 10 mm Hg compared with baseline, in the nebivolol arm (70% vs 55% with enalapril; p = 0.002). A similar trial, using lisinopril 20 mg once daily as the comparator agent, randomized patients to treatment for 12 weeks.³⁴ At the end of the treatment period, a significant reduction in sitting SBP, DBP, and heart rate was demonstrated in both study groups, compared with baseline. There were no significant differences observed between the treatment groups, except that DBP at week 8 was lower with nebivolol. The increased efficacy observed with nebivolol in both the enalapril and lisinopril trials was not associated with an increase in adverse events.

The effects of nifedipine and nebivolol for the treatment of hypertension were compared in 2 studies.^35,36 The larger and more recent study enrolled patients with DBP greater than 94 mm Hg.³⁶ Both nebivolol and long-acting nifedipine effectively lowered trough sitting and standing SBP and DBP, with the only difference between groups being a significantly lower sitting and standing DBP at 2 weeks with nebivolol.

A subsequent study evaluated the antihypertensive effect of nebivolol compared with amlodipine as first-line treatment of hypertension in elderly patients.³⁷ Those with DBP of 95-114 mm Hg were randomly assigned to receive nebivolol 2.5-5 mg or amlodipine 5-10 mg for 12 weeks. The primary index measurement of sitting DBP and SBP at the end of the blinded period was similar with both drugs, but amlodipine did demonstrate significantly lower SBP at weeks 4 and 8. Drug-related adverse events, specifically ankle edema and headache, occurred at a significantly higher rate in the amlodipine group (p < 0.05).

HEART FAILURE
Only 3 ß-adrenergic blockers have shown a mortality benefit for the treatment of heart failure—carvedilol, metoprolol succinate, and bisoprolol. Of those, only carvedilol and metoprolol succinate are approved by the FDA for heart failure treatment. Several smaller studies have evaluated the effects of nebivolol on left ventricular function, establishing significant improvements in ejection fraction and left ventricular mass with treatment.^38-40 SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) was the first trial to assess morbidity and mortality outcomes when nebivolol was added to standard heart failure therapy (Table 1).⁴¹ This randomized, placebo-controlled trial enrolled elderly patients with a history of heart failure. Patients receiving a ß-adrenergic blocker at the time of randomization or those with a previous intolerance or contraindication to a ß-adrenergic blocker were excluded from the study. No additional information was provided in the exclusion criteria or baseline characteristics to address any prior use of ß-adrenergic blockers. Patients were initiated on nebivolol 1.25 mg, with a target dosage of 10 mg once daily; treatment was continued for a mean of 21 months. Baseline characteristics revealed the use of the following other heart failure therapies: diuretics (85%), ACE inhibitors (82%), digoxin (40%), and aldosterone antagonists (38%). The primary endpoint was a composite of all-cause mortality or cardiovascular hospital admission. The mean dose of nebivolol was 7.7 mg, with 80% of patients in that group achieving doses greater than 5 mg.

The primary outcome was reached in 31.1% of patients receiving nebivolol, compared with 65.3% in the placebo group (HR 0.86; 95% CI 0.74 to 0.99), suggesting that 24 patients would need to be treated for 21 months to prevent one occurrence. Secondary outcomes were similar between groups, with the exception of significant reductions in a composite of deaths or hospitalizations for cardiovascular causes with nebivolol treatment.⁴¹ To date, no large, randomized, clinical trial has compared nebivolol with other ß-adrenergic blockers currently indicated for the treatment of heart failure.

	Adverse Effects

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In the clinical studies discussed, nebivolol was well tolerated, and adverse events did not occur more frequently with nebivolol compared with placebo or a comparator agent.^28-33,36,37 Additionally, quality of life showed no impairments with nebivolol treatment when measured with the Inventory of Subjective Health.²⁹ The adverse effects most commonly reported with nebivolol include headache, fatigue, paresthesia, dizziness, and hypotension. Bradycardia can also occur with nebivolol therapy; however, this appears to be dose dependent and, compared with other ß-adrenergic blockers, nebivolol may cause less of a reduction in heart rate.³⁰ There have been no reported adverse effects of nebivolol on cholesterol lipoproteins in clinical trials; other ß-adrenergic blockers appear to have a more adverse effect on lipoproteins than does nebivolol.^{31,35,36,42,43} Similarly, nebivolol has not been shown to affect glucose levels or insulin sensitivity adversely.^42,43

	Drug Interactions and Precautions

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Published data on the drug interaction potential of nebivolol are scarce. There is a potential risk of drug interactions, given that the drug is extensively metabolized in the hepatic system and is a substrate for CYP3A4. One study demonstrated that cimetidine, a potent CYP3A4 inhibitor, had an inhibitory effect on nebivolol metabolism, but there were no associated changes in pharmacodynamic effects because resting blood pressure and heart rate remained unchanged.²⁶ This could suggest that interactions with nebivolol via the cytochrome P450 system will be minimal, as this pathway is only one of several by which the drug is metabolized. As with other ß-adrenergic blockers, caution should be exercised in patients with severe bronchospastic disease and concomitant use of other drugs that cause negative inotropic and chronotropic effects (eg, verapamil, diltiazem, digoxin, amiodarone).

	Dosage and Administration

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For the treatment of hypertension, the dose most commonly used in clinical trials was 5 mg daily; higher doses showed no appreciable further decrease in blood pressure. Nebivolol's long half-life and oral bioavailability allow for once daily dosing to achieve a constant blood pressure-lowering effect. As initiation of ß-adrenergic blockers in patients with heart failure can worsen symptoms, patients should be initiated on a lower dose (eg, nebivolol 1.25 mg) and titrated every 2-4 weeks to a target dose of 10 mg. Nebivolol is under review by the FDA; therefore, dosing recommendations and dosage form availability for the US are not available.

	Discussion

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Nebivolol has been shown to be as effective as other antihypertensive therapies at lowering blood pressure. Additionally, a decrease in all-cause mortality and cardiovascular hospital admissions has been documented versus placebo when nebivolol is used in heart failure patients. Although the oral bioavailability and half-life of nebivolol may differ based on genetic polymorphisms in drug metabolism, any pharmacodynamic differences that may ensue have not been elucidated in clinical trials. Ongoing trials are evaluating nebivolol and its effects in African American patients with hypertension, on insulin sensitivity, and for long-term treatment of hypertension compared with metoprolol.^44-46

The nitric oxide-mediated vasodilation with nebivolol is a unique property that could play a promising role in the long-term treatment of conditions such as hypertension and heart failure, due to the potential benefits on preserving endothelial function. There is renewed interest in the pathophysiologic role of decreased nitric oxide bioavailability secondary to new evidence suggesting that certain patient populations are at higher risk and may have a more favorable response to therapies that target the nitric oxide pathway.⁴⁷ The mortality benefit of this effect will need to be evaluated in long-term studies.

	Conclusions

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Nebivolol is a novel ß-adrenergic blocker that possesses unique pharmacologic properties, compared with other agents in its class. Nebivolol appears to be as effective as other antihypertensive agents at lowering blood pressure and possesses benefits for patients with heart failure. Additional studies are needed to address the long-term benefits of nebivolol for hypertension, to compare nebivolol with other ß-adrenergic blockers for heart failure, and to investigate the clinical relevance of nitric oxide-mediated vasodilation.

	References

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