Clinical Pharmacology of Bosentan, a Dual Endothelin Receptor Antagonist

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 125 mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30 L 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 600 mg (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 beta-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 >300 mg 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 concentratio...

Acute Effect of Sildenafil Is Maintained in Pulmonary Arterial Hypertension Patients Chronically Treated With Bosentan

“…6) Therefore, it is conceivable that the pharmacological effects of bosentan, including its side effects, are enhanced when one of the two drugs is added to the other. On the other hand, the chronic use of bosentan induces the over-expression of CYP3A4, 7) and in fact the plasma concentration of sildenafil has been reported to be reduced when sildenafil is additionally co-prescribed to patients chronically taking bosentan. 8) Nonetheless, the combination of bosentan and sildenafil appears to be safe and some degree of additional benefit has been reported in a subanalyzed section of the Early study 2) and open-label studies.…”

“…It is widely recognized, although not yet reported in Japanese PAH patients, that long-term treatment with bosentan induces the overexpression of CYP3A4 in the liver, 4,7) which is the main enzyme that metabolizes both sildenafil and bosentan, 7,13) and has been shown to reduce the C max and AUC of sildenafil in PAH patients 8) as well as healthy volunteers. 6) The rates of reduction in C max and AUC of sildenafil by bosentan therapy were reported to be 45-56% and 53-69%, respectively, for PAH patients, 8) and 55% and 63%, respectively, for healthy volunteers.…”

Inhalation of the ETAreceptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction

“…Since the inhalation of ET A receptor antagonists targets the pulmonary vasculature directly, it allows the reduction of the effective dose compared with intravenous or oral application. This way, inhaled treatment is also expected to reduce side effects like headache, nausea, nasal congestion, increased amino transferases, peripheral edema, and anemia, as have been reported following prolonged oral application of bosentan (8), or of the novel ET A receptor antagonist sitaxsentan (1,24). In particular, when bosentan has been orally applied in mountaineers at high altitude to prevent acute mountain sickness, the beneficial effects on the pulmonary arterial pressure were opposed by an increase in fluid retention, which might enhance the risk for pulmonary edema formation (17).…”

Successful treatment of severe portopulmonary hypertension in a patient with Child C cirrhosis by Sildenafil

“…Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of metabolites formed by cytochrome P450; mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics and should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. 2 Data have been published on the efficacy and safety of Bosentan in portopulmonary hypertension in Child A and B cirrhosis; [3][4][5][6] there no reports in C stage.…”

“…José Luis Callejas Rubio, MD 1 Javier Salmeró n Escobar, MD 2 Jorge Gonzá lez-Calvín, MD 2 Norberto Ortego Centeno, MD 1 Unit of Autoimmune Diseases …”