|Systematic (IUPAC) name|
|Mol. mass||454.906 g/mol|
|Bioavailability||70 to 100%|
|Metabolism||Hepatic (CYP2C9- and CYP3A4-mediated)|
|Half life||10 hours|
|Excretion|| Renal (50 to 60%)|
Fecal (40 to 50%)
Sitaxsentan or sitaxsentan sodium (actual INN: sitaxentan) (marketed as Thelin® by Encysive Pharmaceuticals) is a small molecule sodium salt that blocks the action of endothelin (ET) on the endothelin-A (ETA) receptor selectively (by a factor of 6000 compared to the ETB). It is a sulfonamide class endothelin receptor antagonist (ERA) and is undergoing Food and Drug Administration (FDA) review for treating pulmonary hypertension. The rationale for benefit compared to bosentan, a nonselective ET blocker, is negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation. However, in clinical trials, the efficacy of sitaxsentan has been much the same as bosentan, but the liver toxicity has been better. Therefore sitaxsentan is expected to be marketed as a safer drug than bosentan, but not necessarily more effective.
Thelin has been approved for marketing in both the European Union (on 10 August, 2006), in Canada and in Australia (on 7 March, 2007). It is already marketed in Germany, The Netherlands, the United Kingdom, and Ireland. The medication is currently undergoing phase III clinical trials within the United States.
On the Prescription Drug User Fee Act (PDUFA) target action date of 24 March, 2006 the United States' FDA recommended an approvable status to Thelin® but said it would not yet approve the product. On July 24, 2006 Thelin received a second approvable letter stating that efficacy outcome issues raised in the context of the STRIDE-2 study were still unresolved. In July 2007, Encysive commenced a formal dispute resolution process in a preliminary meeting with the FDA.
Adverse effects observed with Thelin® are class effects of endothelin receptor antagonists, and include :
- liver enzyme abnormalities (increased ALT and AST)
- nasal congestion
- upper respiratory tract infection
Because Thelin® inhibits metabolism of warfarin, a decreased dose of warfarin is needed when co-administered with thelin. This is due to the fact that warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.
- ↑ UPDATE 1-Encysive gets Canadian approval for hypertension drug. Reuters (May 30, 2007).
- Girgis RE, Frost AE, Hill NS, Horn EM, Langleben D, Mc Laughlin VV, Oudiz RJ, Robbins IM, Seibold JR, Shapiro S, Tapson VF, Barst RJ. 'Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease' ARD 2007 [0: ard.2007.069609v2]
- ATS 2005. The International Conference of the American Thoracic Society. 20 May - 25 May, 2005. San Diego, CA.
- American Heart Association. Primary or Unexplained Pulmonary Hypertension
- Barst RJ, Langleben D, Frost A et al. Sitaxsentan therapy for pulmonary arterial hypertension. American Journal of Respiratory Critical Care Medicine 2004 15 February, 2004 ;169(4):441-7. Electronic publication 20 November, 2003.
- Robyn J. Barst, MD; Stuart Rich, MD, FCCP; Allison Widlitz, MS, PA; Evelyn M. Horn, MD; Vallerie McLaughlin, MD and Joyce McFarlin, RN : Clinical Efficacy of Sitaxsentan, an Endothelin-A Receptor Antagonist, in Patients With Pulmonary Arterial Hypertension Chest. 2002;121:1860-1868.
Medications used in the management of pulmonary arterial hypertension (B01, C02)
|Prostacyclin analogues||Beraprost, Epoprostenol, Iloprost, Treprostinil|
|Endothelin receptor antagonists||Ambrisentan, Bosentan, Sitaxsentan|
|PDE5 inhibitors||Sildenafil, Tadalafil|
|Adjunctive therapy||Calcium channel blockers, Diuretics, Digoxin, Oxygen therapy, Warfarin|
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