Bosentan

Source: Wikipedia, the free encyclopedia.

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)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide
JSmol)
SMILES
  • 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

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 (

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

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,

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

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

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
    . 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. PMID 26109864
    .
  7. ^ "Approved Risk Evaluation and Mitigation Strategies (REMS)". U.S. Food and Drug Administration (FDA). Retrieved 6 August 2017.
  8. PMID 10869264
    .
  9. PMID 17200683
    .
  10. ^ "patient information leaflets"
  11. S2CID 3039181
    .
  12. S2CID 15463540
    .
  13. S2CID 2625368
    .
  14. PMID 10383925
    .
  15. 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.
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