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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacological Characterization of Indacaterol, a Novel Once Daily Inhaled β₂ Adrenoceptor Agonist, on Small Airways in Human and Rat Precision-Cut Lung Slices

Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom (R.G.S., A.G.N., P.J.B.); and Novartis Institutes for BioMedical Research, Respiratory Disease Area, Basel, Switzerland (A.T.)

Indacaterol is a novel once daily inhaled β₂ adrenoceptor agonist in clinical development. This study compared the properties of indacaterol with salmeterol, formoterol, and albuterol on small airways in precision-cut lung slices from human and rat contracted with carbachol and serotonin, respectively. In human lung slices, the rank order of potency was formoterol salmeterol > indacaterol > albuterol, respectively. Indacaterol had similar intrinsic efficacy to formoterol, followed by albuterol and salmeterol. The onset of action was fast for albuterol, formoterol, and indacaterol, whereas it was significantly slower for salmeterol. The duration of action ranking was indacaterol > salmeterol > formoterol > albuterol. When compared with human lung slices, in the rat lung slices, similar potency, intrinsic efficacy, and onset of action were observed for indacaterol, formoterol, and salmeterol. Albuterol had an increased potency when compared with human lung slices and a slower onset of action. In conclusion, our results show that the human lung slice system seems to be a good model to study the clinical properties of inhaled long-acting β₂ adrenoceptor agonists and that caution is needed extrapolating from rat model to humans. Finally, using the human lung slice model, we have characterized indacaterol as a fast acting compound with a longer duration of action than salmeterol and formoterol.

Address correspondence to: Alexandre Trifilieff, Novartis Pharma AG, WSJ-386.12.16, P. O. Box, CH-4002 Basel, Switzerland. E-mail: alexandre.trifilieff{at}novartis.com