Bosentan

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][2][6]

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]

Bosentan causes harm to fetuses (teratogenic) and it may render hormonal contraceptives ineffective.^[4][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.^[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][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.^[4][2]

Bosentan may render hormonal contraceptives ineffective.^[4][2]

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]

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.^[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]

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.^[2][5]