Clinical pharmacology of tezosentan, a dual endothelin receptor antagonist, in patients with liver cirrhosis

Abstract

Tezosentan (T) is a dual endothelin (ET) receptor antagonist, formulated for parenteral use and excreted unchanged in bile. Since ET‐1 may play a role in the pathogenesis of ascites and portal hypertension, cirrhosis and its complications may form an indication for T. The objectives of this study were to explore the tolerability, pharmacokinetics, and pharmacodynamics of T in patients with moderate/severe liver cirrhosis (Child‐Pugh B‐C). Each patient (total n=25) received 2 consecutive 24‐h infusions of 0.2 and 1.0 or 1.0 and 5.0 mg/h of T or placebo. Blood pressure was monitored and blood samples were taken for measurement of T and ET‐1. T was well tolerated (mainly mild headache as adverse event) and induced small dose‐dependent reductions in blood pressure. T showed dose‐proportional, 2‐compartment pharmacokinetics: rapid distribution and slower elimination. Its exposure was dependent on the baseline bilirubin level. For bilirubin levels < 3 and 3.5–12 mg/dl, the exposure to T was 3.3 and 8.5 fold that in healthy subjects (historical control), due to reduced clearance. Compared to patients with acute heart failure, the relative exposure was 1.2 and 3.2 fold, respectively. Exposure to ET‐1 increased dose proportionally and an indirect response model could describe the relationship between T and ET‐1. The IC50 was independent of the severity of the disease. In conclusion, adjustment of the dosing regimen of T in cirrhotic patients, based on bilirubin levels, is warranted. Clinical Pharmacology & Therapeutics (2004) 75, P31–P31; doi: