Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2006) 80, 246–256; doi: 10.1016/j.clpt.2006.05.013
Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients
Patricia N. Sidharta PharmD1, Frank D. Wagner MD, PhD1, Holger Bohnemeier MD1, Arvid Jungnik MD1, Atef Halabi MD1, Stephan Krähenbühl MD, PhD1, Harbajan Chadha-Boreham PhD1 and Jasper Dingemanse PharmD, PhD1
1Actelion Pharmaceuticals Ltd, Allschwil; Charité Universitätsmedizin, Berlin, Germany; PHAROS GmbH, Ulm, Germany; IKP GmbH, Kiel, Germany; and Departments of Clinical Pharmacology and Toxicology and Research, University Hospital Basel, Basel, Switzerland.
Correspondence: Patricia N. Sidharta, PharmD, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland E-mail: patricia.sidharta@actelion.com
Received 20 January 2006; Accepted 18 May 2006.
Abstract
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.
