Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary artery hypertension. It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer. Bosentan is available as film-coated tablets or as dispersable tablets for oral suspension. The dispersable tablets should be dispersed in a small amount of water before administration.
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. Bosentan causes harm to fetuses and pregnant women must not take it, and women must not become pregnant while taking it. It may render hormonal contraceptives ineffective so other forms of birth control must be used. In the US it is only available from doctors who follow an FDA-mandated risk evaluation and mitigation strategywith respect to risks to fetuses and its risks of causing liver damage. The doctor must document a negative pregnancy test for women before prescribing the drug, counsel about contraception, and give regular pregnancy tests. Because there is a high risk that bosentan causes liver damage, the REMS plan also requires pre-testing for elevated transaminases and regular testing while the drug is being taken. Bosentan is also contraindicated in patients taking glyburide due to an increased risk of increased liver enzymes and liver damage when these two agents are taken together.
Adverse effects
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. Very common adverse effects include headache, elevated transaminases, and edema. Common adverse effects 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.
Mechanism of action
Bosentan is a competitive antagonist of endothelin-1 at the endothelin-A and endothelin-B receptors. Under normal conditions, endothelin-1 binding of ET-A receptors causes constriction of the pulmonary blood vessels. 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 and tissue. 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.
Pharmacokinetics
Absolute bioavailability of bosentan is about 50% in healthy subjects. 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. Bosentan is a substrate of CYP3A4 and CYP2C9. CYP2C19 may also play a role in its metabolism. It is also a substrate of the hepatic uptake transporter organic anion-transporting polypeptides OATP1B1, OATP1B3, and OATP2B1. Elimination of bosentan is mostly hepatic, with minimal contribution from renal and fecal excretion. Use of bosentan with cyclosporine is contraindicated because cyclosporine A has been shown to markedly increase serum concentration of bosentan.
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; as of 2001 the results of that trial had not been published. It was approved for PAH in the US in 2001 and in Europe in 2002. By 2013 worldwide sales of bosentan were $1.57 billion. The patents on bosentan started expiring in 2015.
