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

S. Jabbal, A. Manoharan, B. J. Lipworth (Lead / Corresponding author)

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Abstract

Background: Tiotropium is a long acting antimuscarinic (LAMA), licenced 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 down-regulation and associated tolerance induced by LABA.

Objective: We hypothesise this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy.

Methods: 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 4 weeks with challenge performed after 1st and last doses at trough.

Results: 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 IND (P<0.005) or IND/TIO (P<0.05).

Conclusion & Clinical Relevance: Our data suggests 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.
Original languageEnglish
Pages (from-to)1239-1245
Number of pages7
JournalClinical and Experimental Allergy
Volume47
Issue number10
Early online date30 Jun 2017
DOIs
Publication statusPublished - Oct 2017

Fingerprint

Asthma
Mannitol
Muscarinic Antagonists
Receptor Cross-Talk
Tiotropium Bromide
indacaterol
Albuterol
Cross-Over Studies
Adrenal Cortex Hormones
Therapeutics
Down-Regulation

Keywords

  • airway
  • hyperresponsiveness
  • long acting beta 2 agonist
  • Long acting muscarinic antagonist

Cite this

@article{3622fe87caa34013858a6cf3eb71c4c7,
title = "Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma",
abstract = "Background: Tiotropium is a long acting antimuscarinic (LAMA), licenced 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 down-regulation and associated tolerance induced by LABA.Objective: We hypothesise this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy.Methods: 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 4 weeks with challenge performed after 1st and last doses at trough.Results: 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 IND (P<0.005) or IND/TIO (P<0.05).Conclusion & Clinical Relevance: Our data suggests 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.",
keywords = "airway, hyperresponsiveness, long acting beta 2 agonist, Long acting muscarinic antagonist",
author = "S. Jabbal and A. Manoharan and Lipworth, {B. J.}",
note = "Funding: Funded by a departmental unrestricted educational grant",
year = "2017",
month = "10",
doi = "10.1111/cea.12972",
language = "English",
volume = "47",
pages = "1239--1245",
journal = "Clinical and Experimental Allergy",
issn = "0954-7894",
publisher = "Wiley",
number = "10",

}

TY - JOUR

T1 - Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma

AU - Jabbal, S.

AU - Manoharan, A.

AU - Lipworth, B. J.

N1 - Funding: Funded by a departmental unrestricted educational grant

PY - 2017/10

Y1 - 2017/10

N2 - Background: Tiotropium is a long acting antimuscarinic (LAMA), licenced 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 down-regulation and associated tolerance induced by LABA.Objective: We hypothesise this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy.Methods: 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 4 weeks with challenge performed after 1st and last doses at trough.Results: 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 IND (P<0.005) or IND/TIO (P<0.05).Conclusion & Clinical Relevance: Our data suggests 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.

AB - Background: Tiotropium is a long acting antimuscarinic (LAMA), licenced 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 down-regulation and associated tolerance induced by LABA.Objective: We hypothesise this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy.Methods: 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 4 weeks with challenge performed after 1st and last doses at trough.Results: 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 IND (P<0.005) or IND/TIO (P<0.05).Conclusion & Clinical Relevance: Our data suggests 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.

KW - airway

KW - hyperresponsiveness

KW - long acting beta 2 agonist

KW - Long acting muscarinic antagonist

U2 - 10.1111/cea.12972

DO - 10.1111/cea.12972

M3 - Article

C2 - 28665534

VL - 47

SP - 1239

EP - 1245

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

SN - 0954-7894

IS - 10

ER -