Bosentan
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| Clinical data | |
|---|---|
| Trade names | Tracleer, Stayveer, Safebo |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a605001 |
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| Routes of administration | By mouth |
| ATC code | |
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| Pharmacokineticdata | |
| Bioavailability | 50% |
| Protein binding | >98% |
| Metabolism | Liver |
| Eliminationhalf-life | 5 hours |
| Identifiers | |
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| DrugBank | |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.171.206 |
| Chemical and physical data | |
| Formula | C27H29N5O6S |
| Molar mass | 551.62g·mol−1 |
| 3D model (JSmol) | |
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Bosentan,sold under the brand nameTracleeramong others, is a dualendothelin receptor antagonistmedication used in the treatment ofpulmonary artery hypertension(PAH).[4][5]
Bosentan is available as film-coated tablets (62.5 mg or 125 mg) or as dispersable tablets for oral suspension (32 mg).[4]
Medical uses
[edit]Bosentan is used to treat people with moderatepulmonary arterial hypertensionand to reduce the number of digital ulcers — open wounds on especially on fingertips and less commonly the knuckles — in people withsystemic scleroderma.[4][3][6]
Contraindications
[edit]Bosentan is contraindicated in people takingglyburidedue to an increased risk of increased liver enzymes and liver damage when these two agents are taken together.[4]
Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.[4]
Adverse effects
[edit]Bosentan causes harm to fetuses (teratogenic) and it may renderhormonal contraceptivesineffective.[4][3]
In the US it is only available from doctors who follow an FDA-mandatedrisk evaluation and mitigation strategy(REMS) with respect to risks to fetuses and its risks of causing liver damage.[7]
In addition to the risk of causing birth defects and of causing liver damage, bosentan has a high risk of causingedema,pulmonary veno-occlusive disease,decreasing sperm counts, and decreases inhemoglobinandhematocrit.[4][3]
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.[4][3]
Drug interactions
[edit]Bosentan may renderhormonal contraceptivesineffective.[4][3]
Mechanism of action
[edit]Bosentan is a competitive antagonist ofendothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A receptors causesconstriction of the pulmonary blood vessels.[8]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.[9]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.[4]
Pharmacokinetics
[edit]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.[10]
Absolute bioavailability of bosentan is about 50% in healthy subjects.[11]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.[4]
Bosentan is a substrate ofCYP3A4andCYP2C9.CYP2C19may also play a role in its metabolism.[4]It is also a substrate of the hepatic uptake transporter organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1.[12][13]
Elimination of bosentan is mostly hepatic, with minimal contribution from renal and fecal excretion.[14]
Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.[4]
History
[edit]Bosentan was studied inheart failurein a trial called REACH-1 that was terminated early in 1997, due to toxicity at the dose that was being studied.[15]
It was approved for pulmonary artery hypertension in the US in November 2001,[4][16]and in the European Union in May 2002.[3][5]
Society and culture
[edit]Economics
[edit]By 2013, worldwide sales of bosentan were $1.57 billion. The patents on bosentan started expiring in 2015.[17]
References
[edit]- ^"FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)".nctr-crs.fda.gov.FDA.Retrieved22 October2023.
- ^"Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017".Therapeutic Goods Administration (TGA).21 June 2022.Retrieved30 March2024.
- ^abcdefg"Tracleer (bosentan) 62.5 mg and 125mg film-coated tablets".UK Electronic Medicines Compendium. May 2017. Archived fromthe originalon 27 July 2020.Retrieved6 August2017.
- ^abcdefghijklmno"Tracleer- bosentan tablet, film coated Tracleer- bosentan tablet, soluble".DailyMed.15 June 2020.Retrieved15 October2020.
- ^abc"Tracleer EPAR".European Medicines Agency(EMA).17 September 2018.Retrieved16 October2020.
- ^Abraham S, Steen V (2015)."Optimal management of digital ulcers in systemic sclerosis".Therapeutics and Clinical Risk Management.11:939–47.doi:10.2147/TCRM.S82561.PMC4474386.PMID26109864.
- ^"Approved Risk Evaluation and Mitigation Strategies (REMS)".U.S.Food and Drug Administration(FDA).Retrieved6 August2017.
- ^Givertz MM, Colucci WS, LeJemtel TH, Gottlieb SS, Hare JM, Slawsky MT, et al. (June 2000)."Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure".Circulation.101(25): 2922–7.doi:10.1161/01.CIR.101.25.2922.PMID10869264.
- ^Hynynen MM, Khalil RA (January 2006)."The vascular endothelin system in hypertension--recent patents and discoveries".Recent Patents on Cardiovascular Drug Discovery.1(1): 95–108.doi:10.2174/157489006775244263.PMC1351106.PMID17200683.
- ^"patient information leaflets"
- ^Weber C, Schmitt R, Birnboeck H, Hopfgartner G, van Marle SP, Peeters PA, et al. (August 1996). "Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects".Clinical Pharmacology and Therapeutics.60(2): 124–37.doi:10.1016/S0009-9236(96)90127-7.PMID8823230.S2CID3039181.
- ^Jones HM, Barton HA, Lai Y, Bi YA, Kimoto E, Kempshall S, et al. (May 2012). "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.doi:10.1124/dmd.111.042994.PMID22344703.S2CID15463540.
- ^Treiber A, Schneiter R, Häusler S, Stieger B (August 2007). "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.doi:10.1124/dmd.106.013615.PMID17496208.S2CID2625368.
- ^Weber C, Gasser R, Hopfgartner G (July 1999). "Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects".Drug Metabolism and Disposition.27(7): 810–5.PMID10383925.
- ^Packer M, McMurray J, Massie BM, Caspi A, Charlon V, Cohen-Solal A, et al. (February 2005). "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.doi:10.1016/j.cardfail.2004.05.006.PMID15704058.
- ^"Drug Approval Package: Tracleer (Bosentan) NDA #21-290".U.S.Food and Drug Administration(FDA).20 November 2001.Retrieved16 October2020.
- ^Helfand C (2015)."The top 10 patent losses of 2015: Tracleer".FiercePharma.
