Influence of Liver Cirrhosis on the Pharmacokinetics, Pharmacodynamics, and Safety of Tezosentan

This study investigates the pharmacokinetics, pharmacodynamics, and safety of the parenteral endothelin receptor antagonist tezosentan in patients with Child-Pugh classification B/C liver impairment. Cohorts I and II consist of 5 and 11 patients, respectively, with low serum bilirubin (<= 3.0 mg/dL) who receive intravenous tezosentan at 0.2 mg/h for 24 hours followed by 1.0 mg/h for 24 hours (cohort I) or 1.0 mg/h for 24 hours followed by 5.0 mg/h for 24 hours (cohort II). Cohort III (5 patients) receives the same treatment as cohort II but patients have high serum bilirubin (3.5-12 mg/dL). Each cohort includes 1 or 2 placebo patients (in total 4 patients). Compared with a historical control group of healthy subjects, the exposure to tezosentan is 3.1- and 8.5-fold greater in cohorts II and III, respectively. Patients are more sensitive than healthy subjects to the pharmacodynamic effects of tezosentan, as reflected in increases in endothelin-1 concentrations. Tezosentan is well tolerated. Decreases in blood pressure are similar in patients treated with tezosentan or placebo. Moderate/severe liver impairment is associated with increased exposure to tezosentan, which is more pronounced in patients with elevated bilirubin levels, necessitating dose reduction.