Chemistry:Bosentan
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| Trade names | Tracleer, Stayveer, Safebo |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a605001 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 50% |
| Protein binding | >98% |
| Metabolism | Liver |
| Elimination half-life | 5 hours |
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| Formula | C27H29N5O6S |
| Molar mass | 551.62 g·mol−1 |
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Bosentan, sold under the brand name Tracleer among others, is a dual endothelin receptor antagonist medication used in the treatment of pulmonary artery hypertension (PAH).[2][3]
Bosentan is available as film-coated tablets (62.5 mg or 125 mg) or as dispersable tablets for oral suspension (32 mg).[2]
Medical uses
Bosentan is used to treat people with moderate pulmonary arterial hypertension and to reduce the number of digital ulcers — open wounds on especially on fingertips and less commonly the knuckles — in people with systemic scleroderma.[2][1][4]
Pregnancy
Bosentan causes harm to fetuses and pregnant women must not take it, and women must not become pregnant while taking it (Pregnancy Category X). It may render hormonal contraceptives ineffective so other forms of birth control must be used.[2][1]
In the US it is only available from doctors who follow an FDA-mandated risk evaluation and mitigation strategy (REMS) with respect to risks to fetuses and its risks of causing liver damage. The doctor must document a negative pregnancy test for women before prescribing the drug, counsel about contraception, and give regular pregnancy tests.[5]
Contraindications
Because there is a high risk for bosentan to cause liver damage, the FDA's REMS plan also requires pre-testing for elevated transaminases and regular testing while the drug is being taken.[5] Bosentan is also contraindicated in patients taking glyburide due to an increased risk of increased liver enzymes and liver damage when these two agents are taken together.[2]
Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.[2]
Adverse effects
In addition to the risk of causing birth defects and of causing liver damage, bosentan has a high risk of causing edema, pulmonary veno-occlusive disease, decreasing sperm counts, and decreases in hemoglobin and hematocrit.[2][1]
Very common adverse effects (occurring in more than 10% of people) include headache, elevated transaminases, and edema. Common adverse effects (between 1% and 10% of people) include anemia, reduced hemoglobin, hypersensitivity reactions, skin inflammation, itchiness, rashes, red skin, flushing, fainting, heart palpitations, low blood pressure, nasal congestion, gastro-esophageal reflux disease, and diarrhea.[2][1]
Drug interactions
Bosentan may render hormonal contraceptives ineffective so other forms of birth control must be used.[2][1]
Mechanism of action
Bosentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A receptors causes constriction of the pulmonary blood vessels.[6] Conversely, binding of endothelin-1 to ET-B receptors has been associated with both vasodilation and vasoconstriction of vascular smooth muscle, depending on the ET-B subtype (ET-B1 or ET-B2) and tissue.[7] Bosentan blocks both ET-A and ET-B receptors, but is thought to exert a greater effect on ET-A receptors, causing a total decrease in pulmonary vascular resistance.[2]
Pharmacokinetics
After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life (t1/2) is about 5 hours in healthy adult subjects. The exposure to bosentan after intervenous and oral administration is about 2-fold greater in adult patients with pulmonary arterial hypertension than in healthy adult subjects.[8]
Absolute bioavailability of bosentan is about 50% in healthy subjects.[9] Peak plasma concentration of bosentan with the dispersable tablets for oral suspension is 14% less on average compared to peak concentration of the oral tablets.[2]
Bosentan is a substrate of CYP3A4 and CYP2C9. CYP2C19 may also play a role in its metabolism.[2] It is also a substrate of the hepatic uptake transporter organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1.[10][11]
Elimination of bosentan is mostly hepatic, with minimal contribution from renal and fecal excretion.[12]
Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.[2]
History
Bosentan was studied in heart failure in a trial called REACH-1 that was terminated early in 1997, due to toxicity at the dose that was being studied. [13]
It was approved for pulmonary artery hypertension in the US in November 2001,[2][14] and in the European Union in May 2002.[1][3]
Society and culture
Economics
By 2013, worldwide sales of bosentan were $1.57 billion. The patents on bosentan started expiring in 2015.[15]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Tracleer (bosentan) 62.5 mg and 125mg film-coated tablets". UK Electronic Medicines Compendium. May 2017. https://www.medicines.org.uk/emc/medicine/20423.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 "Tracleer- bosentan tablet, film coated Tracleer- bosentan tablet, soluble". 15 June 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=749e42fb-2fe0-45dd-9268-b43bb3f4081c.
- ↑ 3.0 3.1 3.2 "Tracleer EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/tracleer.
- ↑ "Optimal management of digital ulcers in systemic sclerosis". Therapeutics and Clinical Risk Management 11: 939–47. 2015. doi:10.2147/TCRM.S82561. PMID 26109864.
- ↑ 5.0 5.1 "Approved Risk Evaluation and Mitigation Strategies (REMS)". U.S. Food and Drug Administration (FDA). https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=61.
- ↑ "Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure". Circulation 101 (25): 2922–7. June 2000. doi:10.1161/01.CIR.101.25.2922. PMID 10869264.
- ↑ "The vascular endothelin system in hypertension--recent patents and discoveries". Recent Patents on Cardiovascular Drug Discovery 1 (1): 95–108. January 2006. doi:10.2174/157489006775244263. PMID 17200683.
- ↑ "patient information leaflets"
- ↑ "Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects". Clinical Pharmacology and Therapeutics 60 (2): 124–37. August 1996. doi:10.1016/S0009-9236(96)90127-7. PMID 8823230.
- ↑ "Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data". Drug Metabolism and Disposition 40 (5): 1007–17. May 2012. doi:10.1124/dmd.111.042994. PMID 22344703.
- ↑ "Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil". Drug Metabolism and Disposition 35 (8): 1400–7. August 2007. doi:10.1124/dmd.106.013615. PMID 17496208.
- ↑ "Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects". Drug Metabolism and Disposition 27 (7): 810–5. July 1999. PMID 10383925.
- ↑ "Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study". Journal of Cardiac Failure 11 (1): 12–20. February 2005. doi:10.1016/j.cardfail.2004.05.006. PMID 15704058.
- ↑ "Drug Approval Package: Tracleer (Bosentan) NDA #21-290". 20 November 2001. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-290_Tracleer.cfm.
- ↑ "The top 10 patent losses of 2015: Tracleer". FiercePharma. 2015. http://www.fiercepharma.com/special-report/tracleer.
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