Optimization Of Tissue Targeting Properties Of Macitentan, A New Dual Endothelin Receptor Antagonist, Improves Its Efficacy In A Rat Model Of Pulmonary Fibrosis Associated With Pulmonary Arterial Hypertension

Abstract

Introduction: We investigated the efficacy of macitentan, a new tissue targeting dual endothelin (ET) receptor antagonist, in a model of pulmonary fibrosis associated with pulmonary hypertension and compared it with dual ET receptor antagonist, bosentan. Methods and results: Oral administration of macitentan for 19 days dose-dependently decreased lung hydroxyproline content with a statistically significant effect observed at 30 and 100 mg/kg/day vs. non-treated bleomycin rats (n = 8-12). Overall, macitentan (100 mg/kg/d) consistently inhibited the development of pulmonary fibrosis by 18-27% in three independent studies and decreased right ventricle hypertrophy by 25-28% in two of these three studies. In contrast, bosentan (300 mg/kg/d) inhibited the development of pulmonary fibrosis in only one of the three experiments, by 23%, and had no effect on the development of right ventricle hypertrophy. Administration of radiolabeled 14C-macitentan or 14C-bosentan to bleomycin-treated rats showed greater drug distribution in the lung compared to the distribution in healthy animals. Notably, distribution of macitentan into the parenchyma of bleomycin-treated rats was greater than that of bosentan. Conclusion: Repeated experiments demonstrated that macitentan is more efficacious than bosentan in preventing the development of lung fibrosis and right ventricle hypertrophy. Greater ability of macitentan to distribute into the tissue could explain its improved efficacy profile, as it would achieve a more complete blockade of ET receptors.