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

BackgroundArformoterol is a single-isomer (R,R-formoterol) nebulized long-acting β2-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 μg nebulized arformoterol and 12 and 24 μg racemic formoterol (containing 6 and 12 μg (R,R)-formoterol, respectively) delivered by dry powder inhaler (DPI).MethodsAn 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 μg) and racemic formoterol DPI (12 and 24 μg) 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.ResultsAt steady state, exposure to (R,R)-formoterol was similar following nebulized 15 μg arformoterol (Cmax: 6.5 pg/mL; AUC(0−τ): 56.5 pg h/mL) and 12 μg racemic formoterol DPI (Cmax: 6.2 pg/mL; AUC(0−τ): 46.3 pg h/mL). The geometric mean ratios between these two treatments (90% confidence intervals) for Cmax and AUC(0−τ) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 μg racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: Cmax (10.8 pg/mL) and AUC(0−τ) (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 μg racemic formoterol groups, respectively. Changes in (R,R)-formoterol concentrations over time paralleled changes in FEV1.ConclusionsIn this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 μg arformoterol and 12 μg racemic formoterol DPI, and 40% lower than 24 μg 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.