Review of bosentan in the management of pulmonary arterial hypertension

Abstract

The dual endothelin receptor antagonist, bosentan, is an orally active therapy, which is effective in the treatment of pulmonary arterial hypertension (PAH). This review critically appraises the evidence for the efficacy of bosentan in idiopathic and familial PAH, in PAH associated with connective tissue disease and in PAH which may develop in association with other conditions. Data from the pivotal placebo controlled studies and their open labeled extensions as well as long term survival and quality of life data is presented. Data is also presented on the potential benefit of bosentan in patients with inoperable chronic thromboembolic pulmonary hypertension. The safety and tolerability of bosentan as well as drug interactions are discussed. Dosage recommendations in adults and pediatrics are presented. An algorithm is provided to guide the reader in monitoring potential increases in alanine and aspartate transaminase levels that may occur with bosentan use and the dose adjustments that are recommended as a result of any increase in the levels of these enzymes are shown. Finally, the role of bosentan as part of combination therapy in PAH is examined.

Figure 1

Consequences of endothelial dysfunction on pulmonary vascular smooth muscle showing potential targets for therapy. Three major pathways and associated therapeutic targets in abnormal proliferation and contraction of smooth muscle cells are shown. Dysfunctional endothelial cells have decreased production of prostacyclin and endogenous nitric oxide and increased production of endothelin-1. This imbalance of mediators along with decreased production of vasoactive intestinal peptide (VIP) results in a condition favouring vasoconstriction and proliferation of pulmonary artery smooth muscle cells. In addition to their actions on smooth muscle, these mediators have other properties including antiplatelet effects of nitric oxide and prostacyclin and profibrotic and proinflammatory effects of endothelin. Plus signs denote an increase in intracellular concentration: minus signs reflect blockage of a receptor, inhibition of an enzyme or a decrease in the intracellular concentration. (Modified and published with permission from Humbert, Sitbon et al (2004)). Abbreviations: cGMP cyclic guanosine monophosphate; cAMP, cyclic adenosine monophosphate.

Figure 2

Survival in adult patients with idiopathic pulmonary arterial hypertension treated with first line bosentan therapy compared to predicted survival with conventional therapy according to NIH registry. (Reproduced with permission from McLaughlin et al (2005)).