Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma.

Abstract

Tiotropium is a long acting muscarinic antagonist (LAMA), licensed as triple therapy with inhaled corticosteroid and long-acting beta-agonist (ICS/LABA). There may be a synergistic benefit between LAMA and LABA as a consequence of receptor cross-talk, which in turn could modify beta-2 receptor downregulation and associated tolerance induced by LABA. We hypothesize this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy. We evaluated 14 non-smoking asthmatics using an open-label, randomized crossover design. ICS with Indacaterol and Tiotropium (IND/TIO) vs ICS with Indacaterol (IND) over 4weeks with challenge performed after first and last doses at trough. We found no significant difference in mannitol sensitivity, expressed as the provocative dose of mannitol required to reach a 15% drop in FEV1 , or mannitol reactivity, expressed as the response dose ratio (RDR: max % fall in FEV1 /cumulative dose), when comparing ICS/IND/TIO to ICS/IND. Geometric mean fold differences for RDR comparing single and chronic dosing were 3.26-fold (95% CI 1.46-7.29) and 2.51-fold (95% CI 1.32-4.79) for IND and IND/TIO, respectively. Furthermore, salbutamol recovery post-challenge was significantly blunted after chronic compared to single dosing with either ICS/IND (P<.005) or ICS/IND/TIO (P<.05). Our data suggest that concomitant tiotropium does not modify the bronchoprotective tolerance induced by Indacaterol, in turn suggesting that cross-talk may not be clinically relevant when using triple therapy. This study was registered on clinicaltrials.gov as NCT02039011.