Bosentan
Clinical data
Trade namesTracleer, Stayveer, Safebo
AHFS/Drugs.comMonograph
MedlinePlusa605001
License data
Pregnancy
category
  • AU: X (High risk)
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)[2]
  • UK: POM (Prescription only)[3]
  • US: WARNING[1]Rx-only[4]
  • EU: Rx-only[5]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50%
Protein binding>98%
MetabolismLiver
Elimination half-life5 hours
Identifiers
  • 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.171.206 Edit this at Wikidata
Chemical and physical data
FormulaC27H29N5O6S
Molar mass551.62 g·mol−1
3D model (JSmol)
  • CC(C)(C)c1ccc(cc1)S(=O)(=O)Nc2c(c(nc(n2)c3ncccn3)OCCO)Oc4ccccc4OC
  • InChI=1S/C27H29N5O6S/c1-27(2,3)18-10-12-19(13-11-18)39(34,35)32-23-22(38-21-9-6-5-8-20(21)36-4)26(37-17-16-33)31-25(30-23)24-28-14-7-15-29-24/h5-15,33H,16-17H2,1-4H3,(H,30,31,32) checkY
  • Key:GJPICJJJRGTNOD-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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).[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

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.[4][3][6]

Contraindications

Bosentan is contraindicated in people taking glyburide due 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

Bosentan causes harm to fetuses (teratogenic) and it may render hormonal contraceptives ineffective.[4][3]

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.[7]

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.[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

Bosentan may render hormonal contraceptives ineffective.[4][3]

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.[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

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 of CYP3A4 and CYP2C9. CYP2C19 may 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

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. [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

Economics

By 2013, worldwide sales of bosentan were $1.57 billion. The patents on bosentan started expiring in 2015.[17]

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  3. ^ a b c d e f g "Tracleer (bosentan) 62.5 mg and 125mg film-coated tablets". UK Electronic Medicines Compendium. May 2017. Archived from the original on 27 July 2020. Retrieved 6 August 2017.
  4. ^ a b c d e f g h i j k l m n o "Tracleer- bosentan tablet, film coated Tracleer- bosentan tablet, soluble". DailyMed. 15 June 2020. Retrieved 15 October 2020.
  5. ^ a b c "Tracleer EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 16 October 2020.
  6. ^ 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. PMC 4474386. PMID 26109864.
  7. ^ "Approved Risk Evaluation and Mitigation Strategies (REMS)". U.S. Food and Drug Administration (FDA). Retrieved 6 August 2017.
  8. ^ 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. PMID 10869264.
  9. ^ 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. PMC 1351106. PMID 17200683.
  10. ^ "patient information leaflets"
  11. ^ 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. PMID 8823230. S2CID 3039181.
  12. ^ 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. PMID 22344703. S2CID 15463540.
  13. ^ 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. PMID 17496208. S2CID 2625368.
  14. ^ 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. PMID 10383925.
  15. ^ 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. PMID 15704058.
  16. ^ "Drug Approval Package: Tracleer (Bosentan) NDA #21-290". U.S. Food and Drug Administration (FDA). 20 November 2001. Retrieved 16 October 2020.
  17. ^ Helfand C (2015). "The top 10 patent losses of 2015: Tracleer". FiercePharma.