Abstract
Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH).
Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3–5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure.
Severe renal impairment (creatinine clearance 15–30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases.
Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and β-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin.
In healthy subjects, bosentan doses >300mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.
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Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
Bosentan Randomized Trial of Endothelin Antagonist Therapy.
Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure.
Research on Endothelin Antagonism in Chronic Heart Failure.
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Drs Dingemanse and van Giersbergen are employees of Actelion Pharmaceuticals Ltd.
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Dingemanse, J., van Giersbergen, P.L.M. Clinical Pharmacology of Bosentan, a Dual Endothelin Receptor Antagonist. Clin Pharmacokinet 43, 1089–1115 (2004). https://doi.org/10.2165/00003088-200443150-00003
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DOI: https://doi.org/10.2165/00003088-200443150-00003