Influence of severe renal dysfunction on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist

BACKGROUND: One of the potential indications of bosentan, a dual endothelin receptor antagonist, is chronic heart failure. Patients with chronic heart failure frequently also suffer from impaired renal function. OBJECTIVE: To explore the influence of severe renal dysfunction on the pharmacokinetics and metabolism of bosentan in a monocenter, open label, parallel group study. METHODS: Eight renal patients with creatinine clearance 17 - 27 ml/min and 8 healthy subjects (creatinine clearance 99 - 135 ml/min) received a single oral dose of 125 mg bosentan and plasma samples drawn for up to 36 hours after administration were analyzed for bosentan and 3 metabolites. RESULTS: The pharmacokinetic parameters of bosentan did not differ significantly between the study groups: geometric means (95% confidence interval) for Cmax were 1.8 (1.2 - 2.8) and 1.1 microg/ml (0.74 - 1.7), and for AUC0-infinity 7.2 (5.1 - 10.4) and 6.4 (3.4 - 11.2) microg x h/ml in healthy subjects and renal patients, respectively. Levels of the 3 CYP2C9- and CYP3A4-derived metabolites increased approximately 2-fold in renal patients, both in absolute terms and in relation to the parent compound. In renal patients, the exposure to Ro 48-5033, the only pharmacologically active metabolite, was 13% of that to bosentan. CONCLUSION: Severe renal dysfunction did not affect the pharmacokinetics of bosentan to a clinically relevant extent and, therefore, no dose adjustments are deemed necessary in patients with any grade of renal insufficiency.