Influence of mild liver impairment on the pharmacokinetics of tezosentan, a drug excreted unchanged into bile.
OBJECTIVE
To investigate the effect of mild liver impairment on the pharmacokinetics of tezosentan.


METHODS
Eleven patients with mild liver impairment and eight healthy subjects received an intravenous infusion of 50 mg h-1 tezosentan for 1 h. Plasma and urine concentrations were determined during and following termination of the infusion.


RESULTS
The pharmacokinetic parameters presented as geometric means [95% confidence interval (CI)] for clearance, volume of distribution and terminal half-life were 30 (22, 40) and 42 (36, 48) l h-1, 28 (19, 42) and 19 (16, 23) l, and 4.5 (2.9, 7.0) and 3.6 (2.9, 4.5) h in liver patients and healthy subjects, respectively. The ratios (liver patients/healthy subjects) of these geometric means (95% CI) were 0.71 (0.47, 1.1), 1.5 (0.87, 2.6), and 1.3 (0.69, 2.3), respectively. A two-compartment model accurately fitted the concentration-time data. In both groups approximately 4% of the dose was excreted unchanged into urine.


CONCLUSIONS
Although there was a slight trend towards a decreased clearance, the pharmacokinetics of tezosentan in patients with mild liver impairment were similar to those in healthy subjects. Therefore, no dose adaptation seems to be needed in this patient population.
Dingemanse
Jasper
J
Department of Clinical Pharmacology, Gewerbestrasse 18, 4123 Allschwil, Switzerland. jasper.dingemanse@actelion.com
van Giersbergen
Paul L M
PL
D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008107:Liver Diseases / Q000378:metabolism*; D008875:Middle Aged; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014665:Vasodilator Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan