Mass spectrometry detection of inhaled drug in distal fibrotic lung

Theresia A Mikolasch; Eunice Oballa; Mitra Vahdati-Bolouri; Emily Jarvis; Yi Cui; Anthony Cahn; Rebecca L Terry; Jagdeep Sahota; Ricky Thakrar; Peter Marshall; Joanna C Porter

doi:10.1186/s12931-022-02026-5

Mass spectrometry detection of inhaled drug in distal fibrotic lung

Respir Res. 2022 May 11;23(1):118. doi: 10.1186/s12931-022-02026-5.

Authors

Theresia A Mikolasch^{1

2}, Eunice Oballa³, Mitra Vahdati-Bolouri⁴, Emily Jarvis⁵, Yi Cui⁶, Anthony Cahn³, Rebecca L Terry⁷, Jagdeep Sahota^{8

9}, Ricky Thakrar⁹, Peter Marshall^#¹⁰, Joanna C Porter^#^{8

9}

Affiliations

¹ Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK. t.mikolasch@ucl.ac.uk.
² University College London Hospitals NHS Foundation Trust, London, UK. t.mikolasch@ucl.ac.uk.
³ Discovery Medicine, Clinical Pharmacology and Experimental Medicine, GSK Research and Development, Stevenage, UK.
⁴ Early Development Leader, GSK Research, Stevenage, UK.
⁵ Development Biostatistics, GSK Development, Stevenage, UK.
⁶ Safety and Medical Governance, Pharma Safety, GSK Development, Stevenage, UK.
⁷ Pathology, In Vitro/In Vivo Translation, GSK Research, Stevenage, UK.
⁸ Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK.
⁹ University College London Hospitals NHS Foundation Trust, London, UK.
¹⁰ Bioimaging, In Vitro/In Vivo Translation, GSK Research, Stevenage, UK.

^# Contributed equally.

Abstract

Background: Currently the only available therapies for fibrotic Interstitial Lung Disease are administered systemically, often causing significant side effects. Inhaled therapy could avoid these but to date there is no evidence that drug can be effectively delivered to distal, fibrosed lung. We set out to combine mass spectrometry and histopathology with rapid sample acquisition using transbronchial cryobiopsy to determine whether an inhaled drug can be delivered to fibrotic, distal lung parenchyma in participants with Interstitial Lung Disease.

Methods: Patients with radiologically and multidisciplinary team confirmed fibrotic Interstitial Lung Disease were eligible for this study. Transbronchial cryobiopsies and endobronchial biopsies were taken from five participants, with Interstitial Lung Disease, within 70 min of administration of a single dose of nebulised ipratropium bromide. Thin tissue cryosections were analysed by Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging and correlated with histopathology. The remainder of the cryobiopsies were homogenised and analysed by Liquid Chromatography-tandem Mass Spectrometry.

Results: Drug was detected in proximal and distal lung samples from all participants. Fibrotic regions were identified in research samples of four of the five participants. Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry imaging showed co-location of ipratropium with fibrotic regions in samples from three participants.

Conclusions: In this proof of concept study, using mass spectrometry, we demonstrate for the first-time that an inhaled drug can deposit in distal fibrotic lung parenchyma in patients with Interstitial Lung Disease. This suggests that drugs to treat pulmonary fibrosis could potentially be administered by the inhaled route. Trial registration A prospective clinical study approved by London Camden and Kings Cross Research Ethics Committee and registered on clinicaltrials.gov (NCT03136120).

Keywords: Drug distribution; Interstitial fibrosis; MALDI-MS imaging; Transbronchial cryobiopsy.

Publication types

Clinical Study

MeSH terms

Humans
Lung / pathology
Lung Diseases, Interstitial* / diagnosis
Mass Spectrometry
Prospective Studies
Pulmonary Fibrosis* / diagnostic imaging
Pulmonary Fibrosis* / drug therapy
Pulmonary Fibrosis* / pathology
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Associated data

ClinicalTrials.gov/NCT03136120