Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder Inhalation via aerolizer TM

Abstract

The extremely fast appearance of formoterol in plasma shows the predominance of airways absorption shortly after inhalation. Due to a terminal elimination half-life of about 10 h, sustained systemic concentrations of formoterol are predicted for a twice daily treatment regimen without noteworthy accumulation. The excreted amounts in percent of dose of the enantiomers in urine and the enantiomer ratio are similar to data reported previously after lower doses and suggest linear kinetics for doses between 12 microg and 120 microg of formoterol fumarate. The expected side effects on heart rate, QTc interval, and plasma potassium were small and had no clinical consequences in spite of the very high dose of 120 microg (5 to 10 times the recommended therapeutic dose of Foradil). It should be noted that the impact of high doses may be greater in patients. Nevertheless these findings provide reassurance on the safety margin of formoterol after accidental and intentional overdosing.

In vitro sensitization of human bronchus by β2-adrenergic agonists

“…The ␤ 2 -agonist concentrations that we used to sensitize the bronchi may not be consistent with the in vivo concentrations obtained by actual treatment using ␤ 2 -agonists. In a randomized study comparing clinical efficacy of nebulized vs. intravenous salbutamol in severe acute asthma, Salmeron and colleagues (51) found plasma concentrations of salbutamol on the order of 10 Ϫ5 M. In healthy volunteers, plasma formoterol concentration reached 10 Ϫ9 M after inhalation of a single dose of 120 g of formoterol fumarate (40). Therapeutic plasma concentration of fenoterol of ϳ10 Ϫ8 M was recommended (18), but plasma concentration associated with serious toxicity is not known.…”

Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome

“…The half-life of formoterol is approximately 10 hours (26). Given IP in rats, formoterol remains in the brain past 24 hours after peaking at 3 hours postadministration (24).…”

Effects of Formoterol Inhaled Dry Powder on Exercise Performance in Chronic Obstructive Pulmonary Disease: A Single-Center, Randomized, Double-Blind, Placebo-Controlled, Crossover Study

“…28 Based on pharmacokinetic characteristics, decoupling of the bronchial and muscular effects of formoterol could account for the observed lack of correlation between improvements in bronchial flows and exercise tolerance. 16,17 Furthermore, these effects seem to be dose dependent; formoterol improves lung function parameters with a positive dose-response relationship and exercise capacity with a negative relationship, probably because increased unevenness in ventilation-perfusion ratio at higher doses limits exercise capacity. 29 This study had several limitations.…”

“…16,17 It follows that bronchial and muscle effects might have different time courses. We chose to repeat the tests 30 minutes after inhalation (ie, before maximal bronchodilation) to assess the possibility of an earlier direct metabolic effect.…”