1. Definition:
Ambrisentan is a type A endothelin receptor antagonist that is taken orally. It is used to treat pulmonary arterial hypertension. It is authorized as a single medication in the United States and Europe to enhance exercise ability and postpone clinical deterioration. It's also approved for usage with tadalafil to lower the risk of disease progression, hospitalization and improve exercise capacity. Patients with heritable or idiopathic pulmonary arterial hypertension and those with pulmonary arterial hypertension linked with connective tissue disorders were enrolled in studies to determine the effectiveness of Ambrisentan. The majority of the patients examined had etiologies and symptoms that fell within WHO Functional Class II-III. Ambrisentan works as an endothelin receptor antagonist; it prevents endogenous endothelin peptides from constricting blood vessel muscles.
Figure 1: Ambrisentan tablets
2. Chemical & physical features:
Chemical structure:
Figure 2: Chemical structure of Ambrisentan
Synonyms: Letairis, LU-208075, BSF-208075
Molecular formula: C22H22N2O4
Molecular weight: 378.428
CAS number: 177036-94-1
DrugBank Accession Number: DB06403
Physical appearance: white to off-white, crystalline solid, and in aqueous solutions at low pH.
Water solubility: Insoluble in water
Brand names: Letairis®, Volibris®, Pulmonext®
Ambrisentan 10 Mg Tablet PAH Agents: The ETA receptor is inhibited by Ambrisentan, and the ETA: ETB receptor selectivity ratio for ambrisentan blockage is approximately 200:1.
3. Ambrisentan forms and specifications:
If the first dosage of 5 mg orally once a day is tolerated, try increasing the dose to 10 mg orally once a day. The dosage of either medication may be raised as required and accepted at 4-week intervals when taken with tadalafil.
Renal dose adjustment:
- No adjustments are suggested for mild or moderate impairment.
- Caution is advised in the case of severe renal impairment.
Liver dose adjustment:
- Mild impairment: Dose adjustments may be necessary; however, no precise recommendations have been made. It is advised to proceed with caution.
- Moderate or severe impairment: Not advised for use.
4. Ambrisentan vs Tadalafil:
Ambrisentan works by inhibiting the production of endothelin, which is a chemical produced by the body. Endothelin causes blood vessels to contract. It also promotes aberrant muscle development in the walls of the lungs' blood arteries. The pressure needed to pump blood through the lungs to obtain oxygen rises as the vessel narrows. Ambrisentan lowers pulmonary blood pressure to the heart and improves its function by inhibiting the activity of endothelin.
PDE5 is a chemical generated in the lungs and other areas of the body. It is responsible for the breakdown of cyclic guanosine monophosphate (GMP). The arteries relax and expand as a result of cyclic GMP. PDE5 activity is reduced by tadalafil, allowing more cyclic GMP to reach the arteries in the lungs. The vessels relax and expand as a result of this. The pulmonary blood pressure to the heart is reduced and improved by relaxing and expanding the blood vessels in the lungs. This lowers blood pressure in the lungs, allowing them to be more active.
Studies found that patients with PAH who received first Ambrisentan with tadalafil had a lower chance of clinical failure than those who received either drug alone.
5. Ambrisentan vs Bosentan:
Bosentan and Ambrisentan both operate via the exact mechanism. Although Ambrisentan was comparable to Bosentan in terms of effectiveness, it had superior tolerability in terms of abnormal liver function in PAH patients than Bosentan.
6. Mechanism of action of Ambrisentan:
Endothelin-1 is an endogenous peptide that binds to the Endothelin type A and Endothelin type B receptors in endothelium and vascular smooth muscle. Endothelin-1 levels are higher in individuals with pulmonary arterial hypertension. They are linked to higher right atrial pressure and disease severity. Ambrisentan is one of several novel vasodilator medicines that target the ETA receptor, blocking its activity and reducing vasoconstriction. Phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation are prevented by selective ETA receptor suppression mediated by Ambrisentan.
Figure 3: Mechanism of Ambrisentan
7. Ambrisentan interactions:
126 medications interact with Ambrisentan, with 7 severe, 88 moderate, and 31 minor interactions recognized.
The seven significant interactions:
1- Cyclosporine: Cyclosporine has the potential to substantially raise Ambrisentan levels in the blood. This may increase the chance of severe side effects, including liver issues, anemia, and fluid buildup in the lungs.
2- Leflunomide: When used along with other medicines that may potentially damage the liver, such as Ambrisentan, leflunomide has the potential to cause more severe liver problems.
3- Lomitapide: When Ambrisentan is coupled with Lomitapide, the serum concentration of Ambrisentan may be raised, leading to more risk of toxicity.
4- Mipomersen: Mipomersen may cause liver issues, and using it with other medicines that might harm the liver, such as Ambrisentan, can worsen the condition.
5- Pexidartinib: When Ambrisentan is coupled with Pexidartinib, the excretion of Ambrisentan may be reduced.
6- Teriflunomide: When Ambrisentan is coupled with Teriflunomide, the excretion of Ambrisentan may be reduced
7- Tizanidine: Ambrisentan's hypotensive effects may be enhanced by tizanidine.
8. Ambrisentan manufacturing process:
The production of the compounds and their pharmaceutical intermediates are described using synthetic techniques. Coupling the epoxide of formula III with alcohols or thiols of formula IV is the most common production technique.
9. Ambrisentan uses:
The drug Ambrisentan is used to treat pulmonary arterial hypertension:
• Used in conjunction with tadalafil, it decreases the likelihood of disease progression and hospitalization for worsening PAH and enhances exercise capacity.
• To enhance exercise abilities while preventing clinical deterioration.
Patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or hereditable PAH, or PAH linked with connective tissue disorders, were primarily included in the studies demonstrating the efficacy of the treatment regimen.
10. Ambrisentan cost:
The cost of a supply of 10 ambrisentan oral tablets 5 or 10 mg is approximately $2,456.
11. Ambrisentan dosage:
• Adult dosage: Start with 5 mg of Ambrisentan once a day, with or without 20 mg of tadalafil once a day. If required and tolerated, at 4-week intervals, either the Ambrisentan or tadalafil dosage may be raised to 10 mg ambrisentan or 40 mg tadalafil.
• Reproductive females: Only treat females of reproductive potential with Ambrientan following a negative pregnancy test. During therapy, get monthly pregnancy tests.
Figure 4: Dosage of Ambrisentan + Tadalafil
12. Ambrisentan side effects/toxicity:
Adverse effects:
·Swelling may occur anywhere on the body (fluid retention) within weeks of beginning
Ambrisentan.
·Some men who use a medication similar to Ambrisentan have seen a drop in sperm
counts.
·During the first few weeks after beginning Ambrisentan, it is possible to have low red
blood cell counts (Anemia).
·Peripheral edema, stuffy nose, sinusitis, hot flashes, and flushing are the most frequent adverse effects of Ambrisentan.
Toxicity: Ambrisentan has a significant risk of embryo-fetal harm and is teratogenic. The LD50 was higher than or equivalent to 3160 mg/kg when tested in rats. In two-year oral daily dosage trials in rats and mice, there was no indication of carcinogenic hazard. Exclude pregnancy in females of reproductive potential before starting treatment, utilize appropriate contraceptive techniques, and have monthly pregnancy tests.
13. Ambrisentan package insert:
Ambrisentan package insert. Gilead Sciences, Inc., Foster City, CA; 2009 Aug. Accessed October 2010.
14. Ambrisentan REMS:
Two different REMS studies for Ambrisentan have been approved as part of the approval of the new generics. The first is the Ambrisentan REMS, previously known as the Letairis REMS, which includes the mentioned medication and three short New Drug Applications (ANDAs). The PS-Ambrisentan REMS is the second program; there is presently one ANDA sponsor in this REMS. The PS-Ambrisentan REMS will enable Ambrisentan to be filled in a retail environment, while the Ambrisentan REMS will exclusively use specialist pharmacies.
15. Ambrisentan API price:
The average price of Ambrisentan API is $19.0k (USD/kg).
16. Ambrisentan Active Pharmaceutical Ingredient (API) manufacturers in China.
• Zhejiang Huahai Pharmaceutical Co., Ltd.
Huahai Pharmaceutical Co., Ltd. was established in 1989 in Zhejiang, China. It is committed to providing high-quality medical health products to patients worldwide and continually improving product accessibility to help people live improved lives.
Business Type: Manufacturer
Country: China
Category: Active Pharmaceutical Ingredients
Product Name: Ambrisentan
CAS NO.: 713516-99-5
Standard: In-House
Price (USD): Negotiable
• Beijing Hope Pharmaceutical Co., Ltd.
Beijing Hope Pharmaceutical Co., Ltd. is a high-tech, world-oriented pharmaceutical company established in China. The primary enterprises are R&D, manufacturing & sales, export & import trade of APIs and pis, R&D of novel pharmaceutical preparation technology, and new medication registration. They have a research and development center in Beijing, a pharmaceutical intermediates production base in Hebei and Zhejiang provinces, and a GMP-certified APIs manufacturing facility in Shandong province.
Nature of Business: Manufacturer / Exporters / Suppliers
Country: China
Contact person: Alpha Zhang
Registered address: 309-1/b, Chuangxin Building, No.12 Hongda N. Road, Economic Tech&dev Area, Beijing, China, Beijing, China
Year of establishment: 2005
Legal status of the firm: Corporation/Limited Liability Company
• Beijing Mesochem Pharmaceutical Co., Ltd.
Beijing Mesochem Technology Co., Ltd is based in Yizhuang, a hub for national economic and technical growth and a meeting point for the world's top 500 companies.
Business Type: Manufacturer
Country: China
Product Name: Ambrisentan
Assay: NLT 99.0%
Packing: Plastic bag, aluminum tin, carton barrel.
Storage: Protect from humidity; keep in a dry, cool, and shady place.
Remarks: Used for research and development, technician study, and reprocessing of chemical intermediates.
• Lianyungang Guike Pharmaceutical Co., Ltd.
Lianyungang Guike Pharmaceutical CO., LTD was founded and is run in accordance with GMP guidelines. Manufacturers of muscle relaxants and anticancer medicines, as well as intermediaries.
Business Type: Manufacturer
Country: China
Tel: 86-518-86070855/88
Fax: 86-518-86070852
Address: No.1, Xianfeng Road,Dapu Industry Zone,Lianyungang,Jiangsu, China.
CAS NO.: 177036-94-1
Standard: In-House
16. FAQ
Which parameter must be monitored in a patient taking Ambrisentan?
Patients using Ambrisentan should have their ALT and AST levels checked monthly for indications of liver damage. When beginning rifampicin treatment, patients taking Ambrisentan should be carefully watched.
What type of blocker is Ambrisentan?
Ambrisentan is a type A endothelin receptor antagonist that is selective.
Why does cyclosporine affect Ambrisentan but not other vasodilators?
Cyclosporine has the potential to substantially raise Ambrisentan levels in the blood. This may be related to cyclosporine's suppression of transporters and metabolic enzymes involved in Ambrisentan's pharmacokinetics.
References:
1. https://go.drugbank.com/drugs/DB06403
2. https://pubchem.ncbi.nlm.nih.gov/compound/Letairis
3. https://www.drugs.com/dosage/ambrisentan.html
4. https://pubmed.ncbi.nlm.nih.gov/32161055/
5. https://pubmed.ncbi.nlm.nih.gov/34319626/
6. https://www.drugs.com/drug-interactions/ambrisentan-index.html?filter=3
7. https://patents.google.com/patent/US8962832B2/en
8. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=725d4e73-6c83-477a-adc6-0ae4a133a844
9. https://www.drugs.com/price-guide/ambrisentan
10. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=725d4e73-6c83-477a-adc6-0ae4a133a844
11. https://www.empr.com/home/news/fda-approves-first-generic-versions-of-letairis-adds-new-rems-program/
12. https://www.ema.europa.eu/en
![4- (hydroxymethyl) -5-methyl - [1,3] dioxolane-2-one (used to treat hypertension with drugs olmesart](https://eimg.pharmasources.com/image/product/20241203/9cfb202af46a2a1648bacd8ab5855327png)
(All Rights Reserved)