Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD

Peter A. Williamson, Philip M. Short, Karine L. Clearie, Sriram Vaidyanathan, Thomas C. Fardon, Laura J. Howaniec, Brian J. Lipworth

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    Background: Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.

    Methods: Nineteen patients with COPD (FEV1/FVC ratio < 0.7; FEV1 < 60%) completed a doubleblind randomized crossover trial of tiotropium 18 mu g/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/62 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).

    Results: Mean +/- SEM for age and FEV1 were 65 +/- 2 years and 42 +/- 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV1 (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P = .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.

    Conclusions: Budesonide/formoterol caused an unexpected worsening of MS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta 2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result. CHEST 2010; 38 (3): 595-604

    Original languageEnglish
    Pages (from-to)595-604
    Number of pages10
    JournalChest
    Volume138
    Issue number3
    DOIs
    Publication statusPublished - Sep 2010

    Keywords

    • Impulse oscillometry
    • Forced oscillation
    • Disease
    • Salmeterol
    • Asthma
    • Lung
    • Formoterol
    • Spirometry
    • Plethysmography
    • Receptors

    Cite this

    Williamson, Peter A. ; Short, Philip M. ; Clearie, Karine L. ; Vaidyanathan, Sriram ; Fardon, Thomas C. ; Howaniec, Laura J. ; Lipworth, Brian J. / Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD. In: Chest. 2010 ; Vol. 138, No. 3. pp. 595-604.
    @article{2d40ae1c21c846239819d61680aac41e,
    title = "Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD",
    abstract = "Background: Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.Methods: Nineteen patients with COPD (FEV1/FVC ratio < 0.7; FEV1 < 60{\%}) completed a doubleblind randomized crossover trial of tiotropium 18 mu g/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/62 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).Results: Mean +/- SEM for age and FEV1 were 65 +/- 2 years and 42 +/- 2{\%}, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV1 (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P = .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.Conclusions: Budesonide/formoterol caused an unexpected worsening of MS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta 2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result. CHEST 2010; 38 (3): 595-604",
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    author = "Williamson, {Peter A.} and Short, {Philip M.} and Clearie, {Karine L.} and Sriram Vaidyanathan and Fardon, {Thomas C.} and Howaniec, {Laura J.} and Lipworth, {Brian J.}",
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    Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD. / Williamson, Peter A.; Short, Philip M.; Clearie, Karine L.; Vaidyanathan, Sriram; Fardon, Thomas C.; Howaniec, Laura J.; Lipworth, Brian J.

    In: Chest, Vol. 138, No. 3, 09.2010, p. 595-604.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Paradoxical trough effects of triple therapy with budesonide/formoterol and tiotropium bromide on pulmonary function outcomes in COPD

    AU - Williamson, Peter A.

    AU - Short, Philip M.

    AU - Clearie, Karine L.

    AU - Vaidyanathan, Sriram

    AU - Fardon, Thomas C.

    AU - Howaniec, Laura J.

    AU - Lipworth, Brian J.

    PY - 2010/9

    Y1 - 2010/9

    N2 - Background: Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.Methods: Nineteen patients with COPD (FEV1/FVC ratio < 0.7; FEV1 < 60%) completed a doubleblind randomized crossover trial of tiotropium 18 mu g/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/62 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).Results: Mean +/- SEM for age and FEV1 were 65 +/- 2 years and 42 +/- 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV1 (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P = .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.Conclusions: Budesonide/formoterol caused an unexpected worsening of MS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta 2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result. CHEST 2010; 38 (3): 595-604

    AB - Background: Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.Methods: Nineteen patients with COPD (FEV1/FVC ratio < 0.7; FEV1 < 60%) completed a doubleblind randomized crossover trial of tiotropium 18 mu g/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/62 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).Results: Mean +/- SEM for age and FEV1 were 65 +/- 2 years and 42 +/- 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV1 (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P = .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.Conclusions: Budesonide/formoterol caused an unexpected worsening of MS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect beta 2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result. CHEST 2010; 38 (3): 595-604

    KW - Impulse oscillometry

    KW - Forced oscillation

    KW - Disease

    KW - Salmeterol

    KW - Asthma

    KW - Lung

    KW - Formoterol

    KW - Spirometry

    KW - Plethysmography

    KW - Receptors

    U2 - 10.1378/chest.10-0247

    DO - 10.1378/chest.10-0247

    M3 - Article

    VL - 138

    SP - 595

    EP - 604

    JO - Chest

    JF - Chest

    SN - 0012-3692

    IS - 3

    ER -