24-hour Bronchodilation following a single dose of the novel β 2-agonist olodaterol in COPD

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Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting β(2)-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration. To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat(®) Soft Mist™ Inhaler in COPD patients. A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV(1), FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2μg, 5μg, 10μg and 20μg; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV(1). Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40μg. 36 patients were assigned to treatment; mean baseline prebronchodilator FEV(1) was 1.01L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV(1) post-dose (p<0.001); a clear dose-response relationship was observed, with values ranging from 0.070L for olodaterol 2μg to 0.119L for olodaterol 20μg. Similarly, olodaterol was superior to placebo (p<0.001) in peak FEV(1) (0.121L to 0.213L) and average FEV(1) both during the daytime (0-12h; ranging from 0.099L to 0.184L) and night-time (12-24h; ranging from 0.074L to 0.141L). FVC results were consistent with those observed for FEV(1). Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2μg-40μg; in most patients, no plasma levels could be detected following the 2μg dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events. Olodaterol appears to be a promising long-acting β(2)-adrenoceptor agonist,with bronchodilation maintained over 24h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.