Bosentan

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).^[3][4]

Bosentan

Clinical data
Trade names	Tracleer, Stayveer, Safebo
AHFS/Drugs.com	Monograph
MedlinePlus	a605001
License data	US DailyMed: Bosentan
Pregnancy category	AU: X (High risk)
Routes of administration	By mouth
ATC code	C02KX01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] UK: POM (Prescription only)[2] US: ℞-only[3] EU: Rx-only[4] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	50%
Protein binding	>98%
Metabolism	Liver
Elimination half-life	5 hours
Identifiers
IUPAC name 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]benzenesulfonamide
CAS Number	147536-97-8 Y
PubChem CID	104865
IUPHAR/BPS	3494
DrugBank	DB00559 Y
ChemSpider	94651 Y
UNII	XUL93R30K2
KEGG	D07538 N as monohydrate: D01227 N
ChEBI	CHEBI:51450 Y
ChEMBL	ChEMBL957 Y
CompTox Dashboard (EPA)	DTXSID7046627
ECHA InfoCard	100.171.206
Chemical and physical data
Formula	C27H29N5O6S
Molar mass	551.62 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C)(C)c1ccc(cc1)S(=O)(=O)Nc2c(c(nc(n2)c3ncccn3)OCCO)Oc4ccccc4OC
InChI 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) Y Key:GJPICJJJRGTNOD-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Bosentan is available as film-coated tablets (62.5 mg or 125 mg) or as dispersable tablets for oral suspension (32 mg).^[3]

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.^[3][2][5]

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.^[3]

Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.^[3]

Adverse effects

Bosentan causes harm to fetuses (teratogenic) and it may render hormonal contraceptives ineffective.^[3][2]

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.^[6]

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.^[3][2]

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.^[3][2]

Drug interactions

Bosentan may render hormonal contraceptives ineffective.^[3][2]

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.^[7] 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.^[8] 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.^[3]

Pharmacokinetics

After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life (t_1/2) 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.^[9]

Absolute bioavailability of bosentan is about 50% in healthy subjects.^[10] 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.^[3]

Bosentan is a substrate of CYP3A4 and CYP2C9. CYP2C19 may also play a role in its metabolism.^[3] It is also a substrate of the hepatic uptake transporter organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1.^[11][12]

Elimination of bosentan is mostly hepatic, with minimal contribution from renal and fecal excretion.^[13]

Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.^[3]

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.^[14]

It was approved for pulmonary artery hypertension in the US in November 2001,^[3][15] and in the European Union in May 2002.^[2][4]

Society and culture

Economics

By 2013, worldwide sales of bosentan were $1.57 billion. The patents on bosentan started expiring in 2015.^[16]