Background:As available therapies for IPF often lead to adverse effects & treatment cessation, effective treatment with improved safety and tolerability is needed. The ?-galactoside-binding protein galectin-3 (Gal-3) is involved in IPF pathogenesis by activating macrophages & fibroblasts. GB0139, an inhaled small molecule Gal-3 inhibitor, has shown antifibrotic potential.

Aims and Objectives:We developed pop-PK models to enable exposure-response (ER) analysis of GB0139 & preselected biomarkers.

Methods:The healthy volunteer (HV) pop-PK model used data after single doses of GB0139; while the IPF patient pop-PK model was trained on data from IPF patients receiving GB0139 once daily for 14 days (PK profiles measured on Day 1 & Day 14). Response data included Gal-3 levels in plasma & on the surface of alveolar macrophages (AM) collected by bronchoalveolar lavage at baseline (BL) & on Day 14, & plasma biomarkers pertinent to IPF. The relationship of the changes from BL in response readouts & individual simulated average concentrations (Cavg) was assessed.

Results:A sigmoidal relationship between simulated individual Cavg at steady state in IPF patients & response readouts (YKL-40, AM surface Gal-3 levels) was suggested by the data. For the latter, the best model fit was achieved when considering the BL levels of AM surface Gal-3 in addition to Cavg.

Conclusions:The derived pop-PK models quantified the dose-concentration relationship in HV & IPF patients & enabled simulation of plasma & lung PK, & ER analyses. AM surface Gal-3, the biomarker directly linked to the mode of action of GB0139, correlated with simulated Cavg at steady state.