Sitaxentan

Sitaxentan

File:Sitaxsentan.svg
Systematic (IUPAC) name
N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(6-methyl-2H-1,3-benzodioxol-5-yl)acetyl]thiophene-3-sulfonamide
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: Thelin
Routes of administration	Oral
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability	70 to 100%
Protein binding	>99%
Metabolism	Hepatic (CYP2C9- and CYP3A4-mediated)
Biological half-life	10 hours
Excretion	Renal (50 to 60%) Fecal (40 to 50%)
Identifiers
CAS Number	210421-64-0
ATC code	C02KX03 (WHO)
PubChem	CID 216235
Chemical data
Formula	C18H15ClN2O6S2
Molar mass	454.906 g/mol[[]]

Sitaxentan sodium (sometimes incorrectly spelled Sitaxsentan sodium) is marketed as Thelin, originally by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008.

Sitaxentan (original research code, TBC-11251) is a small molecule that blocks the action of endothelin (ET) on the endothelin-A (ET_A) receptor selectively (by a factor of 6000 compared to the ET_B). 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 ET_B stimulation, such as nitric oxide production and clearance of ET from circulation. However, in clinical trials, the efficacy of sitaxentan has been much the same as bosentan, but the liver toxicity has been better. Dosing is once daily, as opposed to twice daily for bosentan. Therefore the general marketing strategy adopted for sitaxentan is to promote it as a more convenient and potentially safer drug than bosentan, though not necessarily more effective.

Regulatory status

Thelin has been approved for marketing in the European Union (on 10 August 2006), in Canada and in Australia (on 7 March 2007). By February 2008 it had been launched commercially in Germany, Austria, The Netherlands, the United Kingdom, Ireland, France, Spain and Italy.

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 24 July 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. However, in September 2007 the company announced that it was making preparations for another phase III clinical trial (intended to be named STRIDE-5) to overcome the FDA's deficiency claims concerning the New Drug Application, and that it would not pursue the dispute resolution process . However, the takeover by Pfizer resulted in a reconfiguration and extension of these plans, which now include combination therapy with sildenafil. The Sitaxentan Efficacy and Safety Trial With a Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) is an ongoing program of three clinical trials conducted in the United States (ClinicaTtrials.gov identifiers: NCT00795639, NCT00796666 and NCT00796510) with anticipated completion dates between June 2010 and January 2014.

Adverse effects

Adverse effects observed with Thelin are class effects of endothelin receptor antagonists, and include :

• liver enzyme abnormalities (increased ALT and AST)
• headache
• edema
• constipation
• nasal congestion
• upper respiratory tract infection
• dizziness
• insomnia
• flushing

Because Thelin inhibits metabolism of warfarin, a decreased dose of warfarin is needed when co-administered with thelin. This is because warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.

External links

• http://www.drugs.com/nda/thelin_050714.html

References

• Mucke HAM: Sitaxentan for the Oral Treatment of Pulmonary Arterial Hypertension: Benefits from Endothelin Receptor Subtype Selectivity? Clinical Medicine: Therapeutics 2009:1 111–121.
• 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 endothelin A 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.
• 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.
• American Heart Association. Primary or Unexplained Pulmonary Hypertension

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