The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD

Abstract

The aim of this double-blind, double-dummy, cross-over, randomized, pilot study was to compare the acute bronchodilator efficacy of a single dose of formoterol with that of tiotropium in patients with stable chronic obstructive pulmonary disease (COPD). Because the potential of tiotropium for additive effects is yet unknown, the acute effects of adding this anticholinergic agent to formoterol were also explored. A total of 20 outpatients with stable COPD were enrolled. Single doses of 12 μg formoterol, 18 μg tiotropium, and 12 μg formoterol+18 μg tiotropium were given. Serial measurements of FEV₁ were performed over 24 h. Formoterol, either alone or in combination with tiotropium, elicited a significantly faster onset of action and showed a trend for a greater maximum bronchodilation than tiotropium alone. At 24 h, mean FEV₁ continued to be significantly higher than pre-dosing value following tiotropium and formoterol+tiotropium. These findings indicate that formoterol and tiotropium have different profiles that make both agents attractive alternatives in the treatment of stable COPD. Since tiotropium ensures prolonged bronchodilation, whereas formoterol adds fast onset and a greater peak effect, the two drugs appear complementary.

Introduction

The Global Initiative for Obstructive Lung Disease (GOLD) guidelines, the international treatment guidelines issued jointly by the World Health Organization and the National Heart, Lung and Blood Institute, emphasise the role of bronchodilators in symptomatic management of all stages of chronic obstructive pulmonary disease (COPD). Based on publications that appeared after June 2000, the 2003 GOLD Update recommends, for moderate-to-very severe COPD, use of regular treatment with long-acting bronchodilators, including tiotropium, rather than short acting bronchodilators, with the choice depending on the availability of medication and the patient's response [1]. For patients whose conditions are not sufficiently controlled with monotherapy, GOLD guidelines [1] and other current international guidelines for the management of COPD [2], [3], [4], recommend combination therapy with an inhaled anticholinergic and a β₂-adrenoceptor agonist.

Nonetheless, two recent studies, specifically designed to explore the potential differences between tiotropium and salmeterol, seem to indicate a greater efficacy of tiotropium than long-acting β₂-agonists [5], [6]. However, peer-reviewed published studies comparing tiotropium and formoterol are lacking. The different pharmacodynamic profile of formoterol when compared to salmeterol might induce a different type of broncholytic effect, mainly if one considers onset of action or peak bronchodilation [7]. This might drive to a different conclusion compared with salmeterol.

For this reason, in this study we examined the bronchodilator efficacy of single doses of formoterol and tiotropium in patients with stable COPD. Moreover, since the potential of tiotropium for additive effects is still unknown, the acute effects of adding this anticholinergic agent to formoterol were also explored.