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0091270009341181v1
49/10/1168    most recent
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PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacokinetics and Pharmacodynamics of the Urotensin-II Receptor Antagonist Palosuran in Healthy Male Subjects

Patricia N. Sidharta, PharmD, Paul L. M. van Giersbergen, PhD and Jasper Dingemanse, PharmD, PhD

From the Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Switzerland.

Palosuran is a new potent and specific antagonist of the human urotensin II (U-II) receptor (UT receptor). This entry-into-humans study evaluated the tolerability and safety, pharmacokinetics, and pharmacodynamics of palosuran in a double-blind, placebo-controlled, single ascending-dose design. Oral doses of 5 to 2000 mg were given to 9 sequential groups of 8 healthy young men (6 on active drug, 2 on placebo) each. At regular intervals, tolerability and safety parameters and plasma levels of palosuran and U-II were determined. Urine was collected to determine excretion of sodium, potassium, creatinine, and palosuran. In this study, palosuran was well tolerated. No serious adverse events or dose-related adverse events were reported. No treatment-related pattern was detected for vital signs, clinical laboratory parameters, or electrocardiography parameters. After rapid absorption, palosuran displayed a plasma concentration-time profile characterized by 2 peaks at approximately 1 and 4 hours after drug administration. The apparent terminal elimination half-life was approximately 20 hours. AUC and Cmax values increased proportionally with doses up to 500 mg. Excretion of unchanged palosuran in urine was limited. No consistent effect was found on any of the pharmacodynamic variables measured. The results of this entry-into-humans study warrant further investigation of the therapeutic potential of palosuran.

Key Words: Palosuran • urotensin-II • urotensin-II receptor antagonist • pharmacokinetics • pharmacodynamics • entry-into-humans study

Address for reprints: Patricia N. Sidharta, PharmD, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil/Switzerland; e-mail: patricia.sidharta{at}actelion.com.


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