Systemic and bronchodilator effects of inhaled rac‐formoterol in subjects with chronic obstructive pulmonary disease: a dose–response study

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The long-acting inhaled b2-agonist formoterol has systemic effects when taken in high doses.• It can be used as relief medication in asthma and there is interest in this approach in chronic obstructive pulmonary disease (COPD).• Relief medication can involve high doses, and in subjects with COPD who have limited ability to bronchodilate the adverse effects can outweigh the benefits.• There are concerns with the overall safety of high-dose b2-agonists in subjects with COPD, and this study looks at the balance of beneficial and adverse effects of a range of doses of inhaled formoterol. WHAT THIS STUDY ADDS• Among subjects with COPD, high-dose inhaled formoterol produced a dose-related increase in forced expiratory volume in 1 s without a corresponding reduction in dyspnoea or increase in walk distance.• Systemic effects were modest, however, and high doses did not appear to reduce patient satisfaction.• Although further safety data are needed, inhaled formoterol may have a role as relief medication in COPD. AIMSRac-formoterol is effective as maintenance treatment for both asthma and chronic obstructive pulmonary disease (COPD) and is now used as relief therapy in asthma. Using rac-formoterol for relief and maintenance treatment could involve inhalation of high doses, and whether this is of benefit in COPD is uncertain. Our aim was to determine whether higher doses of inhaled rac-formoterol produce systemic adverse effects that outweigh the limited bronchodilator benefit seen in subjects with COPD. METHODSWe examined airway and systemic effects of 6, 12, 24 and 48 mg rac-formoterol and placebo on separate days in 20 subjects with symptomatic COPD [forced expiratory volume in 1 s (FEV1) 47% predicted]. FEV1, oxygen saturation, dyspnoea, 6-min walk distance, patient satisfaction and systemic effects were measured and treatment was assessed against placebo and for dose-response effects. RESULTS FEV1[area under the time-response curve (AUC)] and satisfaction scores increased with all formoterol doses compared with placebo, as did AUC tremor with the 24-and 48-mg doses and AUC heart rate with the 48-mg dose. A dose-response relationship was seen with FEV1 and tremor, but not with satisfaction scores. There was no difference between placebo and rac-formoterol for other variables. CONCLUSIONSOur results show that in patients with COPD rac-formoterol improves FEV1 and patient satisfaction without a corresponding reduction in dyspnoea. Since the systemic effects from a relatively high dose were minimal, its use as relief medication in COPD merits further evaluation.

Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches

“…Conventional dose-ranging trials for bronchodilators, such as those used to evaluate tiotropium, salmeterol and formoterol [ 8 , 10 - 12 , 20 ], rely on hypothesis testing and use of contrast statistics and do not provide a rigorous basis for identification of the minimally effective, optimal or maximum doses. This is due to the low signal-to-noise ratio inherent in the measurement of FEV 1 and the poor precision of the conventional methodologies.…”

“…trough FEV 1 for evaluation of bronchodilators in COPD), a dose response is established and a target dose can be selected as the smallest dose that differs from placebo and has both a clinically relevant effect and an acceptable safety profile [ 7 ]. Several such studies have evaluated dose responses for bronchodilators in patients with COPD [ 8 - 12 ]. In Phase II dose-ranging studies in COPD, indacaterol consistently demonstrated bronchodilator efficacy that was superior to placebo, regardless of the dose tested [ 13 , 14 ].…”

A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β2-adrenergic agonist, in asthma; a Phase II, randomized study

“…The maximum effect achieved soon after dosing, otherwise known as the ‘peak’ effect, is also of interest for efficacy and safety reasons. A very high peak effect may indicate high levels of acute drug exposure that could predispose patients to β-agonist-mediated side effects, such as cardiovascular adverse events, when receiving chronic treatment [ 17 ]. Moreover, the ideal pharmacologic characteristic of a once-daily LABA is a low ‘peak to trough ratio’, ensuring relatively stable lung function throughout the day [ 18 ].…”

A Pharmacological Comparative Study of Arformoterol and Salbutamol Nebulization in the Management of Patients Suffering From Acute Non-Severe Bronchial Asthma

“…Several studies have shown the efficacy of formoterol in acute non-severe asthma, acute severe asthma, exercise induced bronchospasm, childhood asthma, and COPD. [15][16][17][18][19] Although few studies have shown clinically significant improvement in lung function (FEV1) with formoterol when compared with salbutamol, 16 most studies have shown a comparable efficacy. 15,17 Safety of formoterol is also well documented even at high doses in patients with asthma and COPD.…”