The Novel Elastase Inhibitor Bay 85-8501: Bioavailability and Food Effect Study to Evaluate Pharmacokinetics of Tablet Formulations

Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An excess of HNE activity has been implicated in the pathogenesis of inflammatory pulmonary diseases, e.g. bronchiectasis, COPD and pulmonary hypertension. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic option. BAY 85-8501 is a novel, selective and reversible HNE inhibitor with activity in the picomolar concentration range, which reveals target inhibition in the lung and ameliorates pulmonary inflammation in preclinical models. Relative bioavailability of 0.1 and 0.5 mg BAY 85-8501 immediate release tablets (tbl) and influence of concomitant food intake on 0.5 mg tbl was investigated in a 4-fold crossover study in 12 healthy male subjects. Treatments were single doses of tbl 0.1 and 0.5 and oral liquid 0.5 mg fasted and tbl 0.5 mg with food. All treatments were safe and well tolerated, no changes of clinical safety (BP, HR, ECG) and clinical laboratory parameters occurred. Tablet formulations of 0.5 and 0.1 mg revealed a comparable dose-normalized exposure, however, absorption rate was nearly halved for the tablet. Intake of American breakfast reduced the absorption rate (max. concentration (40 %) reached after 4 h), but not its extent. Terminal half-life after 0.5 mg ranged from 110 to 121 h. Bioavailability in terms of AUC was comparable between solution and tablet. Food intake decreased absorption rate, but not absorption extent. Tablets have favorable PK and are safe for further treatment in clinical studies.