Translational study searching for synergy between glycopyrronium and indacaterol

Background QVA149 is a combination of indacaterol and glycopyrronium (Dahl, R. et al. Respir Med 2013;107:1558-67). Aim To investigate the interaction of indacaterol and glycopyrroniumin in inducing acute bronchodilation. Methods Bronchial rings from 6 patients were incubated in Krebs-Henseleit solution (37°C) aerated with O2/CO2 (95/5%) under 0.5–1.0 g tension. The effect of drugs (% maximal response to papaverine) administered alone or in combination at isoeffective concentrations was assessed at sub-maximal contraction (70% maximum, EC 70 ) induced by acetylcholine. Lung function of 16 COPD patients was assessed after inhalation of indacaterol 150µg and glycopyrronium 50µg, alone or in combination. Spirometric data were normalized for the maximal effect induced by salbutamol. Drug mixture effects were analyzed by Bliss Independence (BI) theory. Values ( ex vivo n=3, in vivo n=16) are mean±SEM. Results Both glycopyrronium and indacaterol completely relaxed bronchial rings in a concentration-dependent manner, glycopyrronium was more potent than indacaterol (pD 2 : 8.75±0.04 and 7.68±0.22, respectively; P 30 (BI delta effect: 0.26±0.03, P 1 at 15 min post-administration and additive effect persisted between 5 min and 180 min post-inhalation. Conclusions QVA149 ensures a broncholytic effect that is much broader than what can be observed with the single monocomponents.