American Journal of Cardiovascular Drugs

, Volume 6, Issue 3, pp 189–208


A Review of its Use in Pulmonary Arterial Hypertension and Systemic Sclerosis
Adis Drug Evaluation

DOI: 10.2165/00129784-200606030-00006

Cite this article as:
Oldfield, V. & Lyseng-Williamson, K.A. Am J Cardiovasc Drugs (2006) 6: 189. doi:10.2165/00129784-200606030-00006



Bosentan (Tracleer®), an orally administered dual endothelin (ET)a and ETb receptor antagonist, is indicated in the treatment of pulmonary arterial hypertension (PAH).

The efficacy of oral bosentan 125mg twice daily in improving exercise capacity has been demonstrated in well designed trials in adult patients with idiopathic PAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts, and in other trials in patients with idiopathic PAH or PAH associated with congenital heart disease or HIV infection. The beneficial effects of first-line bosentan treatment may be maintained for up to 1 year in patients with idiopathic PAH or PAH associated with connective tissue disease. Despite the potential for treatment-related teratogenicity and hepatotoxicity, long-term data indicate that bosentan is generally well tolerated at the approved dosages. Although well designed trials are required to establish the efficacy of bosentan versus or in combination with other specific PAH therapies, especially sildenafil, the convenient oral administration and lack of serious injection-related adverse effects may render bosentan preferable to other PAH therapies. Preliminary data indicate that bosentan may be effective in pediatric PAH patients, although randomized trials are required. Furthermore, bosentan may be a useful option for the prevention of digital ulcer development in patients with systemic sclerosis. Thus, in accordance with current clinical guidelines, bosentan is a convenient, effective, and generally well tolerated agent for use in the first-line treatment of class III PAH or second-line treatment of class IV PAH.

Pharmacologic Properties

Bosentan is a competitive, specific, dual ETA and ETB receptor antagonist. It produced a dose-dependent increase from baseline in plasma ET-1 levels in healthy volunteers in vivo and prevented ET-1-mediated cellular proliferation in ex vivo human tissue. In clinical studies in PAH patients, treatment with oral bosentan 125 or 250mg twice daily in adults or 31.25–125mg twice daily in pediatric patients for up to 16 weeks generally improved cardiopulmonary hemodynamic variables. It was teratogenic in rodent studies.

In adults, the maximum plasma bosentan concentration (Cmax) and area under the plasma concentration-time curve (AUC) after single- and multiple-dose administration are dose-proportional within the therapeutic dosage range of bosentan (≤500 mg/day). Steady-state pharmacokinetic parameters are achieved after 3–5 days; Cmax and AUC values are ≤50% smaller after multiple-dose administration than after single-dose administration, possibly because of liver enzyme induction. The absolute bioavailability of bosentan is ≈50% after oral administration of single doses of up to 600mg.

Bosentan is metabolized by the hepatic cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4 to form the two primary metabolites Ro 48-5033 and Ro 47-8634, which are further metabolized to form Ro 64-1056. Ro 48-5033 is the only pharmacologically active metabolite and may produce ≤ 20% of the pharmacologic effects of bosentan. Dose-dependent autoinduction of CYP2C9 and CYP3A4 occurs with repeat bosentan administration, reaching a maximum after 4–5 days. Approximately 95% of bosentan and the metabolites are excreted fecally.

The pharmacokinetic properties of oral bosentan in adult and pediatric PAH patients are broadly similar to those observed in healthy volunteers, except for systemic exposure, which is ≈2-fold greater, and clearance, which is lower, in PAH patients. Exposure to the bosentan metabolites is increased in patients with PAH compared with that in healthy volunteers.

Bosentan may interact with other CYP2C9 or 3A4 substrates, inducers or inhibitors. The use of bosentan is contraindicated in patients receiving concomitant glyburide (glibenclamide) or cyclosporine (ciclosporin), and in patients using oral contraceptives as the sole form of contraception.

Therapeutic Efficacy

The therapeutic efficacy of oral bosentan was evaluated in adult patients with WHO functional class III or IV idiopathic PAH or PAH associated with connective tissue disease in randomized, double-blind, comparative trials. In two multicenter studies, oral bosentan 125 or 250mg twice daily for ≤16 weeks improved exercise capacity (mean 6-minute walking distance) versus placebo. Epoprostenol 12–16 ng/kg/min plus bosentan 125mg twice daily and epoprostenol 12–16 ng/kg/min alone produced similar improvements in exercise capacity and WHO functional class at week 16. The beneficial effects of first-line treatment with bosentan 125mg twice daily on exercise capacity and functional class were maintained for up to 1 year in patients with idiopathic PAH or PAH associated with connective tissue disease, according to data from a noncomparative extension of one of the placebo-controlled trials.

In adult and adolescent patients with PAH associated with Eisenmenger syndrome, treatment with oral bosentan 125mg twice daily for up to 16 weeks improved exercise capacity compared with placebo. Bosentan treatment also improved exercise capacity, Borg dyspnea index, and functional class in patients with class III or IV PAH associated with HIV infection in the noncomparative, multicenter BREATHE (Bosentan Randomized trial of Endothelin Antagonist THErapy)-4 trial. Bosentan did not improve exercise capacity at week 12 in a pharmacokinetic trial in pediatric PAH patients with idiopathic PAH or PAH associated with congenital systemic-to-pulmonary shunts that included secondary efficacy endpoints.

Additionally, in two randomized, double-blind, multicenter trials in patients with systemic sclerosis, oral bosentan 125mg twice daily for up to 32 weeks reduced the number of new digital ulcers, but did not improve time to complete healing of digital ulcers versus placebo.


Treatment with bosentan was generally well tolerated in adult or pediatric PAH patients. The most common treatment-emergent adverse effects with bosentan were headache (22%), nasopharyngitis (11%), flushing (9%), lower limb edema (8%), abnormal hepatic function (8%), hypotension (7%), and palpitations (5%).

Serious, dose-related increases in liver aminotransferase levels occurred in adult and pediatric patients. Liver aminotransferase levels increased to >3-fold the upper limit of normal (ULN) in 12% and 14% of adult PAH patients who received bosentan 125 and 250mg twice daily, respectively, and to >8-fold the ULN in 2% and 7% of bosentan 125 and 250mg twice daily recipients. Bosentan may also decrease hemoglobin levels; a clinically relevant decrease in hemoglobin (≥15% decrease from baseline to <11 g/dL) occurred in 3% of PAH patients who received bosentan 125 and 250mg twice daily versus 1% of placebo recipients.

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Vicki Oldfield
    • 1
  • Katherine A. Lyseng-Williamson
    • 1
  1. 1.Adis International Inc.YardleyUSA

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