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

From Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland (Dr Dingemanse, Dr van Giersbergen); and Clinical Research Services, Kiel, Germany (Dr Halabi).

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.

Key Words: Tezosentan • liver cirrhosis • pharmacokinetics • pharmacodynamics • drug transporter proteins

Address for reprints: Jasper Dingemanse, PhD, Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Gewerbestrasse 16, 4123 Allschwil, Switzerland; e-mail: jasper.dingemanse{at}actelion.com.

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