Bosentan

Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ET_A and ET_B) 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 ET_A and ET_B 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 ischaemia, 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 ET A and ET_B receptors, with a slightly higher affinity for ET_A receptors (K_i = 4.1–43 nanomolar) than for ET_B receptors (K_i = 38–730 nanomolar). Bosentan specifically antagonises ET receptors and does not bind to other receptors.

The pharmacokinetics of bosentan have mainly been documented in healthy subjects. Limited data in patients show that the exposure to bosentan in adult PAH patients is approximately 2-fold greater than in healthy adult subjects.

In healthy subjects, bosentan displays dose- and time-dependent pharmacokinetics. Clearance and volume of distribution decrease with increased intravenous doses and increase with time. After oral administration, the systemic exposure is proportional to dose up to 500 mg. At higher oral doses, C_max and AUC increase less than proportionally to the dose.

Absorption

In healthy subjects, 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 (V_ss) of about 18 litres 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 (t_½) 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 metabolising 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 subjects. 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. In vitro, bosentan inhibits the bile salt export pump in hepatocyte cultures.

In vitro data demonstrated that 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 metabolised 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

Pharmacokinetics were studied in paediatric patients in 4 clinical studies (BREATHE-3, FUTURE 1, FUTURE-3 and FUTURE-4). Due to limited data in children below 2 years of age, pharmacokinetics remain not well characterised in this age category.

Study AC-052-356 (BREATHE-3) evaluated the pharmacokinetics of single and multiple oral doses of the film-coated tablet formulation of bosentan in 19 children aged from 3 to 15 years with PAH who were dosed on the basis of body weight with 2 mg/kg twice daily. In this study, the exposure to bosentan decreased with time in a manner consistent with the known auto-induction properties of bosentan. The mean AUC (CV%) values of bosentan in paediatric patients treated with 31.25, 62.5 or 125 mg twice daily were 3,496 (49), 5,428 (79), and 6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47) ng·h/mL observed in adult patients with PAH receiving 125 mg twice daily. At steady state, the systemic exposures in paediatric patients weighing 10–20 kg, 20–40 kg and >40 kg were 43%, 67% and 75%, respectively, of the adult systemic exposure.

In study AC-052-365 (FUTURE 1), dispersible tablets were administered in 36 PAH children aged from 2 to 11 years. No dose proportionality was observed, as steady-state bosentan plasma concentrations and AUCs were similar at oral doses of 2 and 4 mg/kg (AUC_τ: 3,577 ng·h/mL and 3,371 ng·h/mL for 2 mg/kg twice daily and 4 mg/kg twice daily, respectively). The average exposure to bosentan in these paediatric patients was about half the exposure in adult patients at the 125 mg twice daily maintenance dose but showed a large overlap with the exposures in adults.

In study AC-052-373 (FUTURE 3), using dispersible tablets, the exposure to bosentan in the patients treated with 2 mg/kg twice daily was comparable to that in the FUTURE 1 study. In the overall population (n=31), 2 mg/kg twice daily resulted in a daily exposure of 8,535 ng·h/mL; AUC_τ was 4,268 ng·h/mL (CV: 61%). In patients between 3 months and 2 years the daily exposure was 7,879 ng·h/mL; AUC_τ was 3,939 ng·h/mL (CV: 72%). In patients between 3 months and 1 year (n=2) AUC_τ was 5,914 ng·h/mL (CV: 85%), and in patients between 1 and 2 years (n=7) AUC_τ was 3,507 ng·h/mL (CV: 70%). In the patients above 2 years (n=22) the daily exposure was 8,820 ng·h/mL; AUC_τ was 4,410 ng·h/mL (CV: 58%). Dosing bosentan 2 mg/kg three times daily did not increase exposure; daily exposure was 7,275 ng·h/mL (CV: 83%, n=27).

Based on the findings in studies BREATHE-3, FUTURE 1, and FUTURE-3, it appears that the exposure to bosentan reaches a plateau at lower doses in paediatric 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 paediatric patients.

In study AC-052-391 (FUTURE 4) conducted in neonates, bosentan concentrations increased slowly and continuously over the first dosing interval, resulting in low exposure (AUC_0-12 in whole blood: 164 ng·h/mL, n=11). At steady state, AUC_τ was 6,165 ng·h/mL (CV: 133%, n=7), which is similar to the exposure observed in adult PAH patients receiving 125 mg twice daily and taking into account a blood/plasma distribution ratio of 0.6.

The consequences of these findings regarding hepatotoxicity are unknown. Gender and concomitant use of intravenous epoprostenol had no significant effect on the pharmacokinetics of bosentan.

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 volunteers.

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 in a study including 5 patients with pulmonary hypertension associated with portal hypertension and Child-Pugh class B hepatic impairment, and 3 patients with PAH from other causes and normal liver function. In the patients with Child-Pugh class B liver impairment, the mean (95% CI) steady-state AUC of bosentan was 360 (212–613) ng⋅h/mL, i.e. 4.7 times higher, and the mean (95% CI) AUC of the active metabolite Ro 48-5033 was 106 (58.4–192) ng⋅h/mL, i.e. 12.4 times higher than in the patients with normal liver function (bosentan: mean [95% CI] AUC: 76.1 [9.07–638] ng⋅h/mL; Ro 48-5033: mean [95% CI] AUC 8.57 [1.28–57.2] ng⋅h/ml). Though the number of patients included was limited and with high variability, these data indicate a marked increase in the exposure to bosentan and its primary metabolite Ro 48-5033 in patients with moderate liver function impairment (Child-Pugh class B).

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 subjects 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.

A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellular adenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times the plasma concentrations achieved at the therapeutic dose in humans. In rats, oral administration of bosentan for 2 years produced a small, significant increase in the combined incidence of thyroid follicular cell adenomas and carcinomas in males, but not in females, at plasma concentrations about 9 to 14 times the plasma concentrations achieved at the therapeutic dose in humans. Bosentan was negative in tests for genotoxicity. There was evidence of a mild thyroid hormonal imbalance induced by bosentan in rats. However, there was no evidence of bosentan affecting thyroid function (thyroxine, TSH) in humans.

The effect of bosentan on mitochondrial function is unknown.

Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5 times the plasma concentrations achieved at the therapeutic dose in humans. Teratogenic effects, including malformations of the head and face and of the major vessels, were dose dependent. The similarities of the pattern of malformations observed with other ET receptor antagonists and in ET knock-out mice indicate a class effect. Appropriate precautions must be taken for women of childbearing potential.

Development of testicular tubular atrophy and impaired fertility has been linked with chronic administration of endothelin receptor antagonists in rodents.

In fertility studies in male and female rats, no effects on sperm count, motility and viability, or on mating performance or fertility were observed at exposures that were 21 and 43 times the expected therapeutic level in humans, respectively; nor was there any adverse effect on the development of the pre-implantation embryo or on implantation.

Slightly increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/day (about 4 times the maximum recommended human dose [MRHD] and the lowest doses tested) for two years but not at doses as high as 1,500 mg/kg/day (about 50 times the MRHD) for 6 months. In a juvenile rat toxicity study, where rats were treated from Day 4 post partum up to adulthood, decreased absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. The NOAEL was 21 times (at Day 21 post partum) and 2.3 times (Day 69 post partum) the human therapeutic exposure, respectively.

However, no effects on general development, growth, sensory, cognitive function and reproductive performance were detected at 7 (males) and 19 (females) times the human therapeutic exposure at Day 21 post partum. At adult age (Day 69 post partum), no effects of bosentan were detected at 1.3 (males) and 2.6 (females) times the therapeutic exposure in children with PAH.