In fixed-dose inhaled corticosteroids (ICS) combined with long-acting beta-agonist (LABA) bronchodilators, the airway deposition patterns of the component drugs in various sections of the airway can vary widely. This was among results of a study recently published in the European Journal of Pharmaceutical Sciences.

Combination ICS-LABA drugs form the basis of current treatment for asthma and COPD. But the airway distribution of the receptors for each drug is unique, making delivery to the right receptor hit and miss. To better fine tune drug-receptor delivery, researchers based in Budapest, Hungary, attempted to compare the co-deposition patterns of 2 ICS-LABA medications with the distribution patterns of their corresponding airway receptors using numerical modelling.

The researchers chose 2 widely used combination drugs for their analysis. The first,  Symbicort Turbuhaler, contained budesonide as the ICS and formoterol fumarate dehydrate as the LABA; the second, Relvar Ellipta, contained the fluticasone furoate as the ICS combined with vilanterol (trifenatate) as the LABA. Both combination drugs offered a ready availability of data on their aerodynamic properties.

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A total of 49 patients with chronic obstructive pulmonary disease (COPD) underwent Turbuhaler testing, and 59 patients with COPD were selected for Ellipta. “The amount and size distribution of the particles emitted by [dry powder inhalers] depend on the inhalation profile of the patient,” the authors wrote. They elicited 50% inhalation profiles from airflow measurements taken as each patient inhaled the assigned medication. 

Using a stochastic lung model, the investigators calculated the deposition amount of each component drug in patient airways. They found that the ICS and LABA portions of Symbicort Turbuhaler reached their target receptors uniformly throughout the entire respiratory tract. However, the corticosteroid in Relvar Ellipta delivered its contents up to 25% better than its partner component in the large bronchi but nearly 40% worse in the deeper airways

“Better co-deposition would enhance the synergistic effects between the components, while selective deposition based on receptor distribution would lower it,” wrote the authors. But a perfect match is not an option, and only large clinical trials can uncover the most optimal resolution to the problem, the researchers said.

A key limitation of the study was variability in predicting where in the airway the drugs would be deposited, depending on the model used. To ensure that their conclusions were generalizable, the investigators repeated the simulations using another reliable model, the Multiple-Path Particle Dosimetry Model, which confirmed the trends seen in the original modelling.

“Present results highlight the need for extensive research to elucidate whether each drug component should deposit according to its receptor distribution or similar deposition distribution patterns of the components should be attained to benefit from the synergistic effects documented in the open literature,” the authors explained. “Once this aspect [is] clarified, the next step will be to tailor the aerodynamic properties of each component of combination drugs to yield the desired deposition distribution in the lungs,” they added.


Farkas Á, Horváth A, Tomisa G, et al. Do we really target the receptors? Deposition and co-deposition of ICS-LABA fixed combination drugs. Eur J Pharm Sci. Published online April 12, 2022. doi:10.1016/j.ejps.2022.106186

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