Abstract
This is the first study to compare the relative systemic metabolomic and lipidomic bioactivity dose-responses for ICS.
Plasma for metabolomic and lipidomic analysis was obtained from 54 subjects (GSK study 203162, NCT02991859) who received weekly escalating doses (µg/d) of FF (25,100, 200, 400, 800), FP (50, 200, 500,1000, 2000), BUD (100, 400, 800,1600, 3200) or placebo. Samples (pre & post-dose) were analysed on LC/MS/MS and polar LC-platforms and ions were matched to a library of standards for identification and quantification. Statistical analysis was by repeated measures ANOVA, cross-over model, random forest and principal component analysis using log-transformed data.
Across all ICS and doses, few quantifiable metabolites (n=1971) had significant mean % changes[increases/decreases] (p<0.05) versus placebo: FF
1.32 [0.41/0.91], FP 1.93 [0.41/1.52] and BUD 2.03 [0.61/1.47]. At therapeutic doses, fewer changes were also seen with FF 0.96 [0.36/0.61] versus FP 1.67 [0.46/1.22] and BUD 1.42 [0.56/0.91]. Qualitatively, dose related changes were similar including: reduced adrenal steroids (cortisone, cortisol, pregnenolone, androgens and metabolites), increased plasma amino acids, increased glycolysis, reduced fatty acid β-oxidation and branched chain amino acids. Qualitative differences included: altered secondary bile acid profiles for BUD and FF indicating changes in gut microbiome, significantly lowered neurotransmitters (dopamine metabolites) for BUD.
Our findings support the safety of low/mid ICS therapeutic doses with FF 100 µg/d having least effect on most susceptible pathways involving adrenal steroid metabolites. There were few qualitative differences of note except BUD induced neurotransmitter changes.
Footnotes
Cite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 4781.
This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2020