Pharmacology: Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ETA and ETB) receptors. Bosentan decreases both pulmonary and systemic vascular resistance resulting in increased cardiac output without increasing heart rate.
The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in several cardiovascular disorders and connective tissue diseases, including PAH, scleroderma, acute and chronic heart failure, myocardial ischemia, systemic hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases.
Bosentan competes with the binding of ET-1 and other ET peptides to both ETA and ETB receptors, with a slightly higher affinity for ETA receptors (Ki = 4.1-43 nanomolar) than for ETB receptors (Ki = 38-730 nanomolar). Bosentan specifically antagonizes ET receptors and does not bind to other receptors.
Pharmacokinetics: Absorption: In healthy individual, the absolute bioavailability of Bosentan is approximately 50% and is not affected by food. The maximum plasma concentrations are attained within 3-5 hours.
Distribution: Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.
A volume of distribution (Vss) of about 18 liters was determined after an intravenous dose of 250 mg.
Biotransformation and elimination: After a single intravenous dose of 250 mg, the clearance was 8.2 L/h. The terminal elimination half-life (t½) is 5.4 hours.
Upon multiple dosing, plasma concentrations of Bosentan decrease gradually to 50-65% of those seen after single dose administration. This decrease is probably due to auto-induction of metabolizing liver enzymes. Steady-state conditions are reached within 3-5 days.
Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4. Less than 3% of an administered oral dose is recovered in urine.
Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is mainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite is greater than in healthy individual. In patients with evidence of the presence of cholestasis, the exposure to the active metabolite may be increased.
Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and the P-glycoprotein. Bosentan inhibits the bile salt export pump in hepatocyte cultures.
Bosentan had no relevant inhibitory effect on the CYP isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, Bosentan is not expected to increase the plasma concentrations of medicinal products metabolized by these isoenzymes.
Pharmacokinetics in special populations: Based on the investigated range of each variable, it is not expected that the pharmacokinetics of Bosentan will be influenced by gender, body weight, race, or age in the adult population to any relevant extent.
Children: Due to limited data in children below 2 years of age, pharmacokinetics remains not well characterized in this age category.
In pediatric patients more than 2 years of age, it appears that the exposure to Bosentan reaches plateau at lower doses in pediatric patients than in adults, and that doses higher than 2 mg/Kg twice daily (4 mg/Kg twice daily or 2 mg/Kg three times daily) will not result in greater exposure to Bosentan in pediatric patients.
Hepatic impairment: In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the pharmacokinetics have been observed. The steady-state AUC of Bosentan was 9% higher and the AUC of the active metabolite, Ro 48-5033, was 33% higher in patients with mild hepatic impairment than in healthy individuals.
The impact of moderately impaired liver function (Child-Pugh class B) on the pharmacokinetics of Bosentan and its primary metabolite Ro 48-5033 was investigated and data indicates a marked increase in the exposure to Bosentan and its primary metabolite, though the number of patients included was limited and with high variability.
The pharmacokinetics of Bosentan have not been studied in patients with Child-Pugh class C hepatic impairment.
Bosentan is contraindicated in patients with moderate to severe hepatic impairment, i.e., Child-Pugh class B or C.
Renal impairment: In patients with severe renal impairment (creatinine clearance 15-30 mL/min), plasma concentrations of Bosentan decreased by approximately 10%. Plasma concentrations of Bosentan metabolites increased about 2-fold in these patients as compared with individuals with normal renal function. No dose adjustment is required in patients with renal impairment. There is no specific clinical experience in patients undergoing dialysis. Based on physicochemical properties and the high degree of protein binding, Bosentan is not expected to be removed from the circulation by dialysis to any significant extent.