A pharmacokinetic/pharmacodynamic study comparing arformoterol tartrate inhalation solution and racemic formoterol dry powder inhaler in subjects with chronic obstructive pulmonary disease - 08/08/11
Corresponding author. Tel.: +15083577320.Abstract |
Background |
Arformoterol 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 1s (FEV1) were compared for 15μg nebulized arformoterol and 12 and 24μg racemic formoterol (containing 6 and 12μg (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 1.4L, 44.4% predicted). Twice-daily treatments included nebulized arformoterol (15μg) and racemic formoterol DPI (12 and 24μg) 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 15μg arformoterol (Cmax: 6.5pg/mL; AUC(0−τ): 56.5pgh/mL) and 12μg racemic formoterol DPI (Cmax: 6.2pg/mL; AUC(0−τ): 46.3pgh/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 24μg racemic formoterol DPI resulted in dose proportionally higher (R,R)-formoterol: Cmax (10.8pg/mL) and AUC(0−τ) (83.6pgh/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 24μg 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 15μg arformoterol and 12μg racemic formoterol DPI, and 40% lower than 24μg 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.
Le texte complet de cet article est disponible en PDF.Keywords : Long-acting beta2-adrenergic agonists, Chronic obstructive pulmonary disease, Inhalation solution, Arformoterol, Enantioselectivity, Pharmacodynamics, Pharmacokinetics
Plan
Vol 21 - N° 4
P. 657-662 - août 2008 Retour au numéro
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