indication

Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).

pharmacology

Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

mechanism of action

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET_A and ET_B receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET_A and ET_B. Bosentan has a slightly higher affinity for ET_A receptors than for ET_B receptors.

toxicity

Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

biotransformation

Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.

absorption

Absolute bioavailability is approximately 50% and food does not affect absorption.

half life

Terminal elimination half-life is about 5 hours in healthy adult subjects.

route of elimination

Bosentan is eliminated by biliary excretion following metabolism in the liver.

drug interactions

Acenocoumarol: Bosentan may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism.

Anisindione: Bosentan may decrease the anticoagulant effect of anisindione by increasing its metabolism.

Atorvastatin: Bosentan may decrease the serum concentration of atorvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if bosentan is initiated, discontinued or dose changed.

Cerivastatin: Bosentan may decrease the serum concentration of cerivastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if bosentan is initiated, discontinued or dose changed.

Cyclosporine: Cyclosporine may increase the effect and toxicity of bosentan.

Dicumarol: Bosentan may decrease the anticoagulant effect of dicumarol by increasing its metabolism.

Ethinyl Estradiol: Bosentan may decrease the contraceptive effect of ethinyl estradiol. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.

Glyburide: Increased risk of hepatic toxicity

Itraconazole: Itraconazole may increase the effect and toxicity of bosentan.

Ketoconazole: Ketoconazole may increase the effect and toxicity of bosentan.

Lovastatin: Bosentan may decrease the serum concentration of lovastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if bosentan is initiated, discontinued or dose changed.

Medroxyprogesterone: Bosentan may decrease the contraceptive effect of medroxyprogesterone. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.

Mestranol: Decreases the effect of contraceptive

Norethindrone: Bosentan may decrease the contraceptive effect of norethindrone. Hormonal contraception should not be relied on alone during concomitant therapy with bosentan.

Simvastatin: Bosentan may decrease the serum concentration of simvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if bosentan is initiated, discontinued or dose changed.

Telithromycin: Co-administration may cause decreased Telithromycin and increased Bosentan plasma concentrations. Consider alternate therapy.

Temsirolimus: Bosentan may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Bosentan. Consider alternate therapy or monitor for changes in Bosentan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Tramadol: Bosentan may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inducer, Bosentan, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Bosentan is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of bosentan by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bosentan if voriconazole is initiated, discontinued or dose changed.

Warfarin: Bosentan may decrease the anticoagulant effect of warfarin by increasing its metabolism.