Functional respiratory imaging to assess the interaction between systemic roflumilast and inhaled ICS/LABA/LAMA

Int J Chron Obstruct Pulmon Dis. 2016 Feb 4;11:263-71. doi: 10.2147/COPD.S93830. eCollection 2016.


Background: Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs).

Methods: Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation. To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively.

Results: The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=-2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group. Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=-5.368, P<0.001). Functional respiratory imaging (FRI)-based aerosol deposition showed that enhanced ventilation leads to more peripheral particle deposition of ICS/LABA/LAMA in the better-ventilated areas (t=2.407, P=0.024). Finally, the study showed that areas receiving more particles have increased FRI-based bronchodilation (t=2.564, P=0.017), leading to an increase in FEV1 (R=0.348, P=0.029).

Conclusion: The study demonstrated that orally administered roflumilast supports the reduction of regional hyperinflation in areas previously undertreated by inhalation medication. The local reduction in hyperinflation induces a redistribution of ventilation and aerosol deposition, leading to enhanced efficacy of the concomitant ICS/LABA/LAMA therapy. FRI appears to be a sensitive tool to describe the mode of action of novel compounds in chronic obstructive pulmonary disease. Future studies need to confirm the enhanced sensitivity and the potential of FRI parameters to act as surrogates for clinically relevant, but more difficult to measure, end points such as exacerbations.

Keywords: FRI; aerosol distribution; modeling; physiology; ventilation.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Administration, Oral
  • Adrenal Cortex Hormones / administration & dosage*
  • Adrenergic beta-2 Receptor Agonists / administration & dosage
  • Aged
  • Aminopyridines* / administration & dosage
  • Aminopyridines* / pharmacokinetics
  • Benzamides* / administration & dosage
  • Benzamides* / pharmacokinetics
  • Bronchodilator Agents / administration & dosage
  • Cyclopropanes / administration & dosage
  • Cyclopropanes / pharmacokinetics
  • Drug Therapy, Combination / methods
  • Female
  • Humans
  • Male
  • Middle Aged
  • Muscarinic Antagonists / administration & dosage*
  • Phosphodiesterase 4 Inhibitors / administration & dosage
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy
  • Pulmonary Disease, Chronic Obstructive* / physiopathology
  • Pulmonary Ventilation / drug effects*
  • Respiratory Function Tests / methods*
  • Severity of Illness Index
  • Tissue Distribution
  • Tomography, X-Ray Computed / methods
  • Treatment Outcome


  • Adrenal Cortex Hormones
  • Adrenergic beta-2 Receptor Agonists
  • Aminopyridines
  • Benzamides
  • Bronchodilator Agents
  • Cyclopropanes
  • Muscarinic Antagonists
  • Phosphodiesterase 4 Inhibitors
  • Roflumilast