Sitaxsentan Sodium (Thelin™)
What it is:
ET is an endogenous peptide vasoconstrictor that is present in excessive concentrations in patients with PAH. Sitaxsentan, an ET-receptor antagonist undergoing FDA review in the US but approved in much of the rest of the developed world, is selective for the ETA receptors. By selectively antagonizing the ETA receptors, sitaxsentan causes pulmonary arterial vasodilation and allows normal functioning of the ETB receptor, thus reducing the effects of ET. Bosentan, a similar drug, targets ETA and ETB receptors.
FDA Approval:
Thelin has been approved for marketing in both the European Union, Germany, The Netherlands, the United Kingdom, Ireland, Canada, Sweden and Australia. The medication is currently undergoing clinical trials within the United States.
THELIN (sitaxsentan sodium) is indicated in WHO functional class II, III and IV (mild to severe symptoms) and is often given in combination with other medications.
Produced By:
Manufactured by Encysive Pharmaceuticals, Houston, Texas.
Dosing:
Treatment with Thelin should only be started and monitored by a doctor who has experience in the treatment of pulmonary arterial hypertension. It is taken as 100 mg (one tablet) a day, with or without food, preferably at the same time of the day, and the dose should not be increased to more than one tablet a day. It should not be taken by patients who have or have had a serious liver problem. If after 12 weeks the patient's condition is getting worse, then the doctor should review the treatment.
Because of the risks of liver injury and birth defects, Thelin is available only through a special restricted distribution.
Potential Benefits:
Thelin may increase exercise tolerance and delay the worsening of pulmonary arterial hypertension. Functional class has also been known to improve in some patients.
How quickly will I respond to Thelin?
This will vary from person to person, but may take many months. Some improvement in exercise tolerance (6-minute walk test results) was observed after 12 weeks in clinical trial.
Risks, Special Monitoring, and Warnings:
Thelin is contraindicated in pregnant women or women intending to become pregnant, nursing women, people with prior liver impairment or elevated liver enzymes, and people taking the drug cyclosporine.
Because liver enzymes rise in some people taking Thelin, monthly liver enzyme test are required.
If you take the drug Warfarin, your dose will be adjusted when you add Thelin to your regiment. See drug information below for a more in-depth discussion of this.
Common Side Effects include:
- Liver enzyme abnormalities (Increases in ALT and SSI)
- Edema
- Constipation
- Nasal congestion
- Upper respiratory tract infection
- Dizziness
- Insomnia
- Flushing
More Serious Side Effects include:
- Birth defects
- Liver damage
Drug-Drug Interactions
Cyclosporine: THELIN 100 mg once daily co-administered with cyclosporine 3.5 mg/kg twice daily did not alter the pharmacokinetic disposition of cyclosporine, which is extensively metabolized by CYP3A4/5. However, this co-administration resulted in a 6-fold increase in the pre-dose concentrations of sitaxsentan. The mechanism for this interaction is not known. Because of this increase in sitaxsentan exposure, the use of THELIN in patients receiving cyclosporine is contraindicated.
Warfarin: Sitaxsentan is an inhibitor of CYP2C9 and increases the AUC and Cmax of drugs metabolized by CYP2C9. The AUC8 of S-warfarin was increased by approximately 96%, and clearance was decreased by approximately 63% when a single 25 mg dose was co-administered with THELIN 100 mg once daily. An enhanced effect on PT and INR was observed, consistent with the increase in exposure to S-warfarin.
In clinical trials, it was recommended that the warfarin dose be decreased by 80% when starting THELIN and then increased in increments of no greater than 0.5 mg/day while titrating to the desired INR. The mean dose of warfarin at study endpoint in STRIDE 2 (18 weeks of dosing) was 2.2 mg/day for patients receiving THELIN, compared to 3.6 mg/day for patients treated with placebo. In STRIDE 2, the need to change the warfarin dose due to changes in INR was similar among the THELIN-treated and, placebo-treated patients.
Cost:
The cost of Thelin varies from country to country. It has not been priced for the U.S. market.
Because Thelin® is classified as a drug, instead of a treatment, it is covered differently by insurance companies and Medicare. Co-pay rates varied widely. At this time, arrangements with individual insurance companies vary.
Resources include:
Medwire.com
American Thoracic Society
Clinical Trial Results
Recent items from the PHCentral Newsroom:
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Early Data Show Potential For Imatinib To Treat Life-Threatening Form Of Pulmonary Artery Disease
(Novartis ) -- An early proof-of-concept study presented today shows promising results for imatinib in the treatment of pulmonary arterial hypertension (PAH), a severe, incurable blood vessel disorder.
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Bayer Reports Progress In Clinical Program For Riociguat
(Bayer) -- Based on positive Phase II trial findings, Bayer Schering Pharma will move into Phase III trials with its oral agent riociguat (BAY 63-2521). Riociguat is the first member of a new class of vasodilating agents called soluble guanylate cyclase (sGC) stimulators. It is being investigated as a new approach for the treatment of different forms of pulmonary hypertension.
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Citrulline And PH
(KDRV ) -- The study drug helps supplement the body with Citrulline, a chemical important in the production of nitric oxide.
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Better Understanding Of Blood Vessel Constrictor Needed To Harness Its Power For Patients
(Medical College of Georgia ) -- To harness endothelin-1's power to constrict blood vessels and help patients manage high blood pressure or heart failure, scientists must learn more about how endothelin functions naturally and in disease states, says a Medical College of Georgia researcher.
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FDA Issues Response to Encysive´s Formal Dispute for Experimental Thelin´s NDA
(NETWORK MEDICA) -- Encysive Pharmaceuticals Inc. announced that it has received a written response from the U.S. Food and Drug Administration (FDA) regarding Encysive´s request for formal dispute resolution on its New Drug Application (NDA) for Thelin (sitaxsentan sodium) for the treatment of pulmonary arterial hypertension (PAH). The FDA issued a fourth "approvable letter," requesting the company for further trials.
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Inhaled Treprostinil New Drug Application Filed By FDA
(United Therapeutics ) -- United Therapeutics Corporation and its wholly-owned subsidiary Lung Rx, Inc. announced today that the U.S. Food and Drug Administration has accepted for review the New Drug Application for inhaled treprostinil for the treatment of pulmonary arterial hypertension. The NDA will be subject to a standard review period of 10 months, with a targeted user fee deadline of April 30, 2009.
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Pulmonary Hypertension Drug (Citrulline)
(WHOI ) -- An earlier study found patients who received citrulline had lower rates of pulmonary hypertension compared to those who received a placebo treatment. Now, a larger, multi-national trial is underway to verify the effects of the drug.
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Bosentan Aids Treprostinil In PAH
(Medscape/Reuters Health ) -- In certain patients with moderate-to-severe pulmonary artery hypertension (PAH), the addition of oral bosentan to subcutaneous treprostinil-based therapy can produce further clinical improvement, investigators report in the July issue of Chest.
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EPIX Pharmaceuticals Initiates Phase 2b Right-Heart Catheterization Study Of PRX-08066 In Patients With COPD And Moderate-to-Severe PH
(EPIX Pharmaceuticals ) -- EPIX Pharmaceuticals, Inc. announced that it has initiated its Phase 2b right-heart catheter study of PRX-08066 in patients with chronic obstructive pulmonary disease (COPD) and moderate-to-severe pulmonary hypertension (PH). PRX-08066 is a novel serotonin type 2B receptor (5-HT2B) antagonist that may represent a new mechanism of action for treating PH.
To learn about other treatments under review for the treatment of PAH, search DRUG TRIALS.
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