Avosentan

1 . Dieterle W, Hengelage T. Absolute bioavailability and pharmacokinetics of avosentan in man. Int J Clin Pharmacol Ther. 2009 Sep;47(9):587-94.
Abstract
OBJECTIVE: Avosentan is a potent, selective endothelin A receptor blocker. The pharmacokinetics of avosentan were investigated in healthy male and female volunteers, following oral and i.v. administration of single doses of avosentan and its absolute bioavailability was determined. METHODS: In a randomized, balanced open-label, three-period oral crossover study, 26 healthy subjects (19 males and 7 females) received Treatments A, B and C. Treatment A consisted of a single dose of a 25 mg film-coated tablet of avosentan, Treatment B of a single dose of a 50 mg film-coated tablet of avosentan and Treatment C of 10 mg avosentan in 20 ml solution for infusion for 20 minutes (10 mg avosentan in 20 ml phosphate buffer pH 9.0 containing 1% polysorbate 20). Plasma concentrations of avosentan and its hydroxymethyl metabolite Ro 68-5925 were measured by liquid chromatography-tandem mass spectrometry. RESULTS: The absolute bioavailability values (compared with i.v. infusion) for the 25 and 50 mg film-coated tablets were 81% and 72%, respectively. The extent of absorption, as measured by partial and total AUC, increased almost proportionally with the dose. The estimated proportionality coefficient for AUC0- yen was 1.12 (90% CI 1.06, 1.18). For the rate of absorption (Cmax) strict dose-proportionality was not demonstrated (proportionality coefficient 1.13 (90% CI 1.0, 1.28)). No relevant gender differences in the pharmacokinetic characteristics were evident after a single i.v. dose and at an oral dose of 25 mg, whereas after oral administration of 50 mg of avosentan differences were seen in Cmax and t1/2. CONCLUSION: The absolute bioavailability of avosentan film-coated tablets is high, i.e. 70 - 80%.

2 . Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G; ASCEND Study Group. J Am Soc Nephrol. 2010 Mar;21(3):527-35.
Abstract
In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

3 . Konieczka K, Meyer P, Schoetzau A, Neutzner A, Mozaffarieh M, Flammer J. Effect of avosentan (SPP-301) in porcine ciliary arteries. Curr Eye Res. 2011 Feb;36(2):118-24.
Abstract
PURPOSE: To investigate the vasoactive effect of ET(A)-endothelin receptor antagonists avosentan (SPP-301) and BQ-123 in isolated porcine ciliary arteries with and without endothelium. To investigate the effect of avosentan on the endothelin-1 induced contractions in comparison with BQ-123 and BQ-788 (ET(B)-endothelin receptor antagonist) in isolated porcine ciliary arteries with and without endothelium.METHODS: Vessels were placed in a myograph system to measure isometric forces. In a first set of experiments, quiescent vessels were exposed, cumulatively, to increasing concentrations of avosentan and BQ-123 (10(-9) M-3?×?10(-6) M). In a second set of experiments, quiescent vessels were first incubated with avosentan (10(-6) M and 10(-8) M), BQ-123 (10(-6) M), and BQ-788 (10(-6) M), respectively. Then the vessels were exposed, cumulatively, to increasing concentrations of endothelin-1 (10(-12) M-3?×?10(-8) M). Each set of experiments was conducted in the vessels with and without endothelium.RESULTS: Cumulative concentrations of avosentan and BQ-123 had no vasoactive effect in quiescent vessels. Avosentan had a strong inhibitory effect on the endothelin-1-induced contractions. The inhibitory effect of 10(-6) M avosentan was significantly stronger than the effect of 10(-8) M avosentan. The effect of avosentan (10(-6) M) tended to be stronger than the effect of BQ-123 (10(-6) M). To a lesser extent, BQ-788 also had an inhibitory effect on the endothelin-1-induced contractions.CONCLUSIONS: Avosentan has a strong inhibitory effect on the endothelin-1-induced contractions. Blockade of ET receptors is potentially an attractive target in many eye diseases including glaucoma. Further studies are needed to evaluate the usefulness of endothelin blockers in ophthalmology.

4 . Baltatu OC, Iliescu R, Zaugg CE, Reckelhoff JF, Louie P, Schumacher C, Campos LA. Antidiuretic effects of the endothelin receptor antagonist avosentan. Front Physiol. 2012;3:103.
Abstract
Several clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypothesized that avosentan which was described as a predominant ET(A) receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ET(B) receptors may occur. Incremental doses of the predominant ET(A) receptor antagonist SPP301 (0.003; 0.03; 3?mg/kg) were administered intravenously to anesthetized Sprague-Dawley rats undergoing saline diuresis. Diuresis, glomerular filtration rate, and blood pressure (BP) were monitored. SPP301 decreased urine output (5.6; 34.8; 58.8% decrease from vehicle) and fractional excretion of water (5.7; 31.7; 56.4% decrease from vehicle) in a concentration-dependent manner. Glomerular filtration rate was unchanged while BP was reduced by 10?mmHg only by the highest dose of SPP301. Administration of the ET(B) selective receptor antagonist BQ-788 (3?mg/kg) following SPP301 3?mg/kg did not further decrease urine output or water excretion and was without effect on glomerular filtration rate. These data indicate that increasing concentrations of SPP301 may also block ET(B) receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with predominant ET(A) receptor blockers.

5 . Effect of SPP 301, an Endothelin Antagonist, on Intraocular Pressure in Glaucomatous Monkey Eyes By Wang, Rong-Fang; Podos, Steven M.; Serle, Janet B.; Baltatu, Ovidiu C. From Current Eye Research (2011), 36(1), 41-46.
Abstract
Purpose: To evaluate the effect of topical application of avosentan (SPP 301), endothelin receptor type A antagonist, on intraocular pressure (IOP) in monkey eyes with laser-induced unilateral glaucoma. Materials and Methods: A multiple-dose study was performed in eight glaucomatous monkey eyes that were topically treated with SPP 301 by applying a 50 ?l drop (25 ?l?×?2) at 9:30 a.m. and 3:30 p.m. for 5 consecutive days at three concentrations (0.003%, 0.03%, or 0.3%). IOP was measured hourly for 6 hrs on each day of the study beginning at 9:30 a.m. for one baseline day, one vehicle-treated day, and treatment days 1, 3, and 5. Results: Twice daily administration of each of the three concentrations of SPP 301 for 5 days significantly (p?