Arformoterol: The first nebulized long-acting beta2-adrenergic agonist

Dr Abdelghany is adjunct assistant professor of pharmacy practice, School of Pharmacy, University of Connecticut, Storrs, Conn, and coordinator, Investigational Drug Service, Yale-New Haven Hospital, New Haven, Conn. Dr Merl is a pharmacy practice resident, Yale-New Haven Hospital.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airflow limitation that is not fully reversible. It is the fourth-leading cause of death in the United States and is projected to become the third-leading cause of death by 2020.¹ COPD is a major economic burden in the United States, with more than $37 billion spent directly on COPD healthcare expenses and indirectly on COPD morbidity and mortality expenses in 2004.¹

COPD is considered incurable with the currently available treatment options. None of the existing therapies has been demonstrated to prevent the decline in lung function associated with this disease. Currently, the goals of therapy are to prevent or provide relief of symptoms, reduce the frequency and attenuate the severity of exacerbations, prevent disease progression, and maintain or improve quality of life.^2,3

Bronchodilators are considered first-line maintenance therapy in patients with COPD. Long-acting bronchodilators, including long-acting beta₂-adrenergic agonists and inhaled anticholinergic drugs, are more effective than short-acting bronchodilators.⁴ Long-acting beta₂-adrenergic agonists exert their beneficial effect by a reduction in airflow resistance with improvement in lung emptying, which leads to a reduction in resting and dynamic hyperinflation during exercise and improved exercise performance.⁴ The efficacy of long-acting beta₂-agonists in patients with COPD has been demonstrated in several clinical trials. These agents have been demonstrated to decrease daytime and nighttime symptoms and to improve quality of life.⁵

CHEMISTRY AND PHARMACOLOGY

Formoterol enantiomers demonstrate different, possibly contradictory biologic activities. Arformoterol, the (R,R)-enantiomer, is 1,000-fold more potent than the (S,S)-enantiomer, demonstrates 2-fold greater potency than racemic formoterol, and may account exclusively for the activation of beta₂ receptors by the racemic mixture.¹¹ However, (S,S)-formoterol is not biologically inert. It inhibits the beneficial effects of (R,R)-formoterol on proliferation, anti-inflammatory cellular surface marker expression, and cytokine secretion. Results from studies in healthy volunteers have indicated that racemic formoterol may have proinflammatory properties that would mask the beneficial effects associated with beta₂-agonists.¹² Further studies are needed to determine the clinical significance of these properties and to elucidate the advantages of arformoterol over formoterol, if any.

PHARMACOKINETICS

CLINICAL TRIALS

The primary efficacy end point was postdose bronchodilation as measured by the percent change from baseline FEV₁ at the end of the dosing interval (12 hours after evening dose for the BID groups; 24 hours after daily dose for the QD group) over the 12 weeks of treatment. Treatment with arformoterol or salmeterol led to a statistically significant improvement in morning trough FEV₁ over 12 weeks. In both trials, the mean differences of the percent change in morning trough FEV₁ with arformoterol 15 mcg BID, arformoterol 25 mcg BID, arformoterol 50 mcg QD, and salmeterol 42 mcg BID versus placebo after the first dose at Week 0 were 15.3 (95% CI, 12.1–18.4), 19.1 (95% CI, 15.8–22.3), 13.4 (95% CI, 10.2–16.6), and 14.6 (95% CI, 11.5–17.7), respectively. Improvement in morning trough FEV₁ was maintained at Week 12; the mean differences of percent change in morning trough FEV₁ with arformoterol 15 mcg BID, arformoterol 25 mcg BID, arformoterol 50 mcg QD, and salmeterol 42 mcg BID versus placebo at Week 12 were 9.9 (95% CI, 5.9–14.0), 13.1 (95% CI, 8.7–17.5), 10.6 (95% CI, 6.3–15.0), and 10.8 (95% CI, 7.0–14.5), respectively.^6,14

The secondary efficacy end point was the percent change from baseline in 12-hour FEV₁ AUC (% change in FEV₁ AUC_{0–12 h}) over 12 weeks. The mean differences of the percent change in FEV₁ AUC_{0–12 h} with arformoterol 15 mcg BID, arformoterol 25 mcg BID, arformoterol 50 mcg QD, and salmeterol 42 mcg BID versus placebo at Week 12 were 5.9 (95% CI, 3.8–7.9), 5.0 (95% CI, 2.9–7.2), 12.7 (95% CI, 10.3–15.1), and 1.7 (95 % CI, –0.1 to 3.6), respectively.

In these trials, arformoterol doses of 25 mcg BID and 50 mcg QD did not provide sufficient additional benefits on a variety of end points to warrant use of these higher doses. Therefore, a total daily dose >30 mcg is not recommended.

The median time to onset of bronchodilation after the first 15-mcg dose of arformoterol was 6.7 minutes when bronchodilation was defined as an increase in FEV₁ of 15% and was 20 minutes when bronchodilation was defined as an increase in FEV₁ of 12% and 200 mL. Peak bronchodilator effect generally occurred within 1 to 3 hours of dosing.^6,14

Analyses of responders, defined as patients achieving a change from baseline FEV₁ of ≥10% or ≥15%, were performed. Patients in all active treatment groups demonstrated superior responses compared with patients in the placebo group at Weeks 0 and 12. Among those treated with arformoterol 15 mcg BID, a ≥10% improvement in FEV₁ was achieved in 93% of patients after the first dose and in 84% of patients after 12 weeks of treatment. Among those treated with salmeterol 42 mcg BID, 90% achieved a ≥10% improvement in FEV₁ after the first dose, and 62% achieved a ≥10% improvement after 12 weeks of treatment. Among those treated with arformoterol 15 mcg BID, a ≥15% improvement in FEV₁ was achieved in 82% of patients after the first dose and in 63% of patients after 12 weeks of treatment.¹⁴