A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease

Background: Arformoterol is a single-isomer (R,R-formoterol) nebulized long-acting beta(2)-agonist approved for use in patients with chronic obstructive pulmonary disease (COPD). Exposure (plasma concentrations of (R,R)-formoterol) and forced expiratory volume in 1 s (FEV1) were compared for 15 mu g nebulized arformoterol and 12 and 24 mu g racemic formoterol (containing 6 and 12 mu g (R,R)-formoterol, respectively) delivered by dry powder inhaler (DPI). Methods: An open-label, randomized, three-way crossover study in 39 subjects with COPD (FEV1 1.4 L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15 mu g) and racemic formoterol DPI (12 and 24 mu g) for 14 days. Plasma concentrations of (R,R)- and (S,S)-formoterol were determined on days 1 and 14 of each treatment period. Airway function efficacy endpoints included the percent change in trough FEV1 from baseline on day 14 of each treatment period. Results: At steady state, exposure to (R,R)-formoterol was similar following nebulized 15 mu g arformoterol (C-max: 6.5 pg/mL; AUC(0-tau): 56.5 pg h/mL) and 12 mu g racemic formoterol DPI (C-max: 6.2 pg/mL; AUC((0-tau)): 46.3 pg h/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for C-max and AUC((0-tau)) were 0.91 (0.76,1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 mu g racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: C-max (10.8 pg/mL) and AUC((0-tau)) (83.6 pg h/mL). Detectable (S,S)-formoterol was consistently measured only after treatment with racemic formoterol. The mean percent increase in trough FEV1 was 19.1% in the arformoterol group, and 16.0% and 18.2% in the 12 and 24 mu g racemic formoterol groups, respectively. Changes in (R,R)-formoterol concentrations over time paralleled changes in FEV1. Conclusions: In this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 pg arformoterol and 12 mu g racemic formoterol DPI, and 40% lower than 24 mu g racemic formoterol DPI. There was no evidence of chiral interconversion following treatment with arformoterol. Finally, temporal changes in airway function in all treatment groups corresponded to changes in (R,R)-formoterol plasma concentrations. (C) 2008 Elsevier Ltd. All rights reserved.