The Science Journal of the American Association for Respiratory Care

2007 OPEN FORUM Abstracts

PHARMACOKINETICS OF (R,R)- AND (S,S)- FORMOTEROL FOLLOWING SINGLE AND MULTIPLE DOSES OF ARFORMOTEROL INHALATION SOLUTION AND RACEMIC FORMOTEROL DRY POWDER INHALER IN SUBJECTS WITH COPD

J. Kharidia1, C. M. Fogarty2, C. F. LaForce3, G. Maier1, R. Hsu1, K. M. Dunnington4, L. Curry1, J. P. Hanrahan1

Background: Arformoterol is a single isomer (R,R-formoterol) nebulized long-acting beta2-agonist approved for the long-term maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD). This study compared the pharmacokinetics (PK) of (R,R)- and (S,S)-formoterol following treatment with arformoterol 15 µg delivered by nebulization and racemic formoterol 12 and 24 µg (containing 6 and 12 µg (R,R)- and (S,S)-formoterol, respectively) delivered by dry powder inhaler (DPI).

Methods: An open-label, randomized, 3-way crossover study in 39 subjects with COPD (FEV1 1.4L, 44.4% predicted) who received BID treatment with nebulized arformoterol (15 µg in 2 mL) and racemic formoterol DPI (12 µg and 24 µg) for 14 days. Plasma concentrations of (R,R)- and (S,S)-formoterol were determined after the first and last dose.

Results: At steady state, exposure to (R,R)-formoterol was similar following nebulized 15 µg arformoterol (Cmax: 6.5 pg/mL; AUC(0-12): 56.5 pg*hr/mL) and 12 µg racemic formoterol (Cmax: 6.2 pg/mL; AUC(0-12): 46.3 pg*hr/mL). The geometric mean ratios between these 2 treatments (90% confidence intervals) for Cmax and AUC(0-12) were 0.91 (0.76, 1.09) and 1.16 (1.00, 1.35), respectively. Treatment with 24 µg racemic formoterol resulted in dose proportionally higher (R,R)-formoterol Cmax (10.8 pg/mL) and AUC(0-12) (83.6 pg*hr/mL). Measurable (S,S)-formoterol concentrations were observed at steady state only after dosing with 12 µg (Cmax: 7.6 pg/mL; AUC(0-12): 48.5 pg*hr/mL) and 24 µg (Cmax: 14.5 pg/mL; AUC(0-12): 89.7 pg*hr/mL) racemic formoterol. There was no evidence of exposure to (S,S)-formoterol or chiral inversion following dosing with arformoterol.

Conclusions: In this study, plasma exposure to (R,R)-formoterol was similar for nebulized 15 µg arformoterol and 12 µg racemic formoterol, and 60% lower than 24 µg racemic formoterol. (S,S)-Formoterol was detected only after treatment with racemic formoterol. Despite the presence of equivalent proportions of (S,S)- and (R,R)-isomers in the racemate, (S,S)-formoterol levels and PK parameters were as high or higher than those of (R,R)-formoterol.


Mean plasma concentrations over time of (S,S)- and (R,R)-formoterol after 14 days of treatment (S,S)-Formoterol concentrations after arformoterol 15 µg were below the limit of quantification (0.5 pg/mL).
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