Nebulized formoterol fumarate: Dose selection and pharmacokinetics

Abstract To determine a dose of nebulized formoterol fumarate inhalation solution (FFIS) comparable to that of the marketed formoterol fumarate dry powder inhaler (FA, 12 μg), two crossover studies were conducted in subjects with COPD. Study 1 was a single-dose, double-blind, double-dummy dose-ranging study in which 47 subjects were randomly assigned to treatment sequences that evaluated the bronchodilatory effects of FFIS 2.5, 5, 10, 20, and 40 μg, FA, and placebo over 12 h. Mean FEV1 AUC0–12 following FFIS treatment ranged from 1.3 to 3.0 l/h in a dose-related manner, with equivalent values (2.3 l/h) for FFIS 20 μg and FA. Results for other spirometric measures, including peak and trough FEV1 and absolute change in FEV1 by timepoint, confirmed the comparability of FFIS 20 μg and FA. Study results with the nebulized formulation supported the rapid time to onset of bronchodilation with FFIS 20 μg (3.9 and 2.2 min imputed for 15% and 12%/200 ml response, respectively). Study 2, a single-dose, open-label crossover study, was conducted to establish the pharmacokinetic (PK) profile of nebulized formoterol and confirm comparability to FA. Thirteen subjects were randomly assigned to treatment sequences with FFIS 10, 20, and 244 μg and FA with a 5–14-day washout period between each treatment. Formoterol levels were assessed from blood and urine collected pre-dose and over a 24–36-h period after dosing. Pharmacodynamic (PD) measures included clinical laboratory and ECG measures pre-dose and over a 24-h period post-dose. FFIS 244 μg was rapidly absorbed with a Tmax of 12 min and t1/2 of 6.1 h. Data from other doses were sporadic due to assay sensitivity. The mean amount excreted (Ae) in urine suggested linear kinetics and confirmed the comparability of FFIS 20 μg and FA. Mean serum potassium decreased and mean serum glucose increased transiently in a dose-dependent manner following treatment. No clinically significant ECG changes were observed; mean heart rate increased after treatment with FFIS 244 μg by up to 6 bpm. Findings from dose-ranging and PK/PD studies confirmed that a 20 μg dose of FFIS was comparable to formoterol fumarate delivered by dry powder inhalation (12 μg) and established the dose proportionality and linear kinetics of formoterol fumarate delivered by nebulization.