Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients.
OBJECTIVE
In patients with renal disease increased urotensin II plasma levels have been observed. We have investigated whether palosuran, a potent, selective, and competitive antagonist of the urotensin II receptor, has effects in patients who are prone to the development of renal disease.


METHODS
Macroalbuminuric, diabetic patients, categorized by renal function, were treated with oral doses of 125 mg palosuran twice daily for 13.5 days in addition to treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The 24-hour urinary albumin excretion rate was determined twice at baseline and after 13.5 days of treatment. Plasma concentrations of palosuran were determined for 12 hours after the first and last drug intake. Renal hemodynamics was measured before and after 12.5 days of treatment. Tolerability and safety parameters were monitored.


RESULTS
An overall clinically significant reduction of 24.3% (geometric mean) (95% confidence interval, 4.1 to 45.0) in the 24-hour urinary albumin excretion rate was observed (P = .014). No effect was observed on renal hemodynamic parameters. Palosuran was rapidly absorbed with maximum plasma concentrations at 1 hour after drug administration. The accumulation factor was 1.7 (geometric mean) (95% confidence interval, 1.3 to 2.1). Palosuran was well tolerated.


CONCLUSIONS
The good tolerability profile and the decrease in the 24-hour urinary albumin excretion rate may benefit diabetic patients with renal failure with regard to their disease progression. Larger placebo-controlled trials in this patient population are needed to investigate whether urotensin II receptor antagonists, given as monotherapy or combination therapy, may improve the current treatment of diabetic nephropathy.
Sidharta
Patricia N
PN
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. patricia.sidharta@actelion.com
Wagner
Frank D
FD
Bohnemeier
Holger
H
Jungnik
Arvid
A
Halabi
Atef
A
Krähenbühl
Stephan
S
Chadha-Boreham
Harbajan
H
Dingemanse
Jasper
J
D000368:Aged; D000419:Albuminuria / Q000188:drug therapy / Q000517:prevention & control*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006261:Headache / Q000139:chemically induced; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009304:Nasopharyngitis / Q000139:chemically induced; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D012079:Renal Circulation / Q000187:drug effects; D016896:Treatment Outcome; D014508:Urea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014508:Urea; D003404:Creatinine; C493249:1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea