Could Inhaled Therapies be the Future for Fibrosing Lung Conditions?
Both Nintedanib and Pirfenidone are systemic therapies currently licensed for use in idiopathic pulmonary fibrosis [IPF] and other fibrosing lung conditions. Unfortunately, both therapies have significant side effect profiles which can impact patient compliance and quality of life. In an exciting proof of concept study recently study published by the Porter team [Mikolasch et al*], it was demonstrated for the first time that an inhaled drug can be deposited into distal fibrotic lung parenchyma in patients with interstitial lung disease [ILD]. These results suggest that the inhaled therapies could be used to treated fibrosing lung conditions, and thus reduce systemic side effects.
A total of five patients with confirmed fibrotic ILD were recruited into this study, who required transbronchial cryobiopsy (TBC) for diagnostic reasons. All patients received a single dose of 500mcg of nebulised ipratropium bromide 1 hour prior to bronchoscopy, after which transbronchial cryobiopsies and endobronchial biopsies were taken. Ipratropium bromide was chosen for this study for several reasons, including it being a strongly positively charged molecule which in feasibility studies demonstrated good sensitivity to detection by mass spectrometry techniques. It also has robust safety data.
The cryosections were analysed by both Matrix Assisted Laser Desorption/Ionization‑Mass Spectrometry (MALDI-MS) imaging, with correlation with histopathology as well as Liquid Chromatography Mass Spectrometry.
Figure: An example from one patient’s endobronchial sample. From left to right it shows; a photo of the frozen biopsy sample, a mass spectra showing fragment ions, the MALDI- Mass Spectrometry image representing the drug foci regions meeting the selection criteria for positive identification and detection of ipratropium, and finally the corresponding histology image.
The results of this study demonstrate that drug was detected in proximal and distal lung samples from all participants, the latter of which is predominantly affected in IPF. This study demonstrates that for the first time an inhaled drug can deposit into distal, fibrotic lung parenchyma in patients with ILD.
Using this combination of TBC, mass spectrometry and histopathology techniques, we are hoping further research can be conducted into the use of inhaled drugs for the treatment of fibrosing lung conditions.
*Mikolasch TA, Oballa E, Vahdati-Bolouri M, Jarvis E, Cui Yi, Cahn A, Terry RL, Sahota J, Thakrar R, Marshall P, Porter JC. Mass spectrometry detection of inhaled drug in distal fibrotic lung. Respiratory Research. 2022;23:118
Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, Richeldi L, Kolb M, Tetzlaff K, Stowasser S, Coeck C, Clerisme‑Beaty E. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27