Effect of severe renal impairment on the pharmacokinetics and tolerability of the parenteral endothelin antagonist tezosentan.
BACKGROUND
Tezosentan, an endothelin receptor antagonist, is under development for the treatment of acute heart failure. Impaired renal function is a frequent comorbidity in these patients.


OBJECTIVE
To assess the pharmacokinetics and tolerability of tezosentan in 8 patients with severe renal impairment (creatinine clearance < 30 ml/min) compared to 8 healthy subjects.


METHODS
Tezosentan was infused at a rate of 100 mg/h for 1 h. Blood and urine samples were collected for pharmacokinetic determinations. Vital signs, ECG, adverse events and clinical laboratory parameters were monitored to assess tolerability.


RESULTS
The mean (95% confidence interval) volume of distribution and clearance of tezosentan in renal patients were 15 (13, 18) l and 42 (34, 52) l/h, respectively, and did not differ significantly from the values of 18 (15, 20) l and 36 (29, 44) l/h found in healthy subjects. In patients, the renal excretion of tezosentan was impaired. Tezosentan caused a decrease in blood pressure and was well tolerated in both groups.


CONCLUSIONS
No clinically relevant effects of severe renal impairment on the pharmacokinetics and tolerability of tezosentan were found. Therefore, no dose adjustment oftezosentan is deemed necessary in patients with any grade of renal impairment.
van Giersbergen
P L M
PL
Actelion Pharmaceuticals Ltd., Clinical Pharmacology, Allschwil, Switzerland. paul.vangiersbergen@actelion.com
Dingemanse
J
J
D019540:Area Under Curve; D003404:Creatinine / Q000097:blood; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology; D007262:Infusions, Intravenous; D007668:Kidney / Q000503:physiopathology; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000097:blood / Q000503:physiopathology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan; D003404:Creatinine