Tracleer®
Bosentan is an inducer of the cytochrome P450 isoenzymes CYP2C9 and CYP3A4, and, according to in
vitro ,
possibly CYP2C19. Therefore, with the simultaneous use of Tracleer® and drugs whose metabolism is mediated by these isoenzymes, their concentration in the blood plasma decreases. The possibility of reducing the effectiveness of drugs whose metabolism is carried out with the participation of the above isoenzymes should be taken into account. It is possible that after starting to take Tracleer®, changing its dose or discontinuing it, it may be necessary to change the dose of concomitantly used medications.
Bosentan is metabolized by the isoenzymes CYP2C9 and CYP3A4. Inhibition of these isoenzymes may be accompanied by an increase in the concentration of bosentan in the blood plasma (see ketoconazole). The effect of CYP2C9 isoenzyme inhibitors on bosentan plasma concentrations has not been studied. When used simultaneously with them, caution should be exercised.
Fluconazole and other inhibitors of the CYP2C9 and CYP3A4 isoenzymes
: Concomitant use of
bosentan with
fluconazole ,
which mainly inhibits the CYP2C9 isoenzyme and only slightly the CYP3A4 isoenzyme, may be accompanied by a marked increase in the concentration of bosentan in the blood . This combination is not recommended. For the same reason, the simultaneous use of Tracleer® and potent inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole or ritonavir) and an inhibitor of the CYP2C9 isoenzyme (voriconazole) is not recommended.
Cyclosporine A:
simultaneous use of Tracleer® and
cyclosporine A
(calcineurin inhibitor)
is contraindicated
(see section “Contraindications”). When these drugs are taken together, the minimum initial concentration of bosentan in the blood increases by 30 times compared to the use of bosentan alone. The steady-state concentration of bosentan in the blood increases 3-4 times compared to the concentration of bosentan during monotherapy. The mechanism of this interaction is probably the inhibition of the transport protein responsible for the transfer of bosentan into hepatocytes by cyclosporine. The concentration of cyclosporine A (substrate of the CYP3A4 isoenzyme) in the blood is reduced by approximately 50%. This change is most likely due to the induction of the CYP3A4 isoenzyme by bosentan.
Tacrolimus, sirolimus:
simultaneous use with the drug Tracleer® in clinical trials has not been studied, however, it is assumed that the concentration of bosentan in the blood may increase, similar to simultaneous use with cyclosporine A. When used together with the drug Tracleer®, the concentration of tacrolimus and sirolimus in the blood may decrease.
In this regard, Tracleer® should not be
used concomitantly with tacrolimus or sirolimus. If it is necessary to use these drugs simultaneously, it is necessary to monitor the possible development of PLR and monitor the concentrations of tacrolimus and sirolimus in the blood.
Glibenclamide:
simultaneous use of Tracleer® at a dose of 125 mg 2 times a day for 5 days was accompanied by a decrease in the concentration of glibenclamide (CYP3A4 isoenzyme substrate) in the blood by 40% and a possible significant decrease in the hypoglycemic effect of the drug. Blood concentrations of bosentan were also reduced by 29%. In addition, in patients receiving combination therapy, the frequency of increased liver transaminase activity increased. Both glibenclamide and bosentan have an inhibitory effect on the bile salt export pump (BSEP), which may explain the increase in liver transaminase activity. This combination is not recommended. There are no data on drug interactions between bosentan and other sulfonylureas.
Rifampicin:
with simultaneous use of the drug Tracleer® at a dose of 125 mg 2 times a day and rifampicin, which is a powerful inducer of the CYP2C9 and CYP3A4 isoenzymes, in 9 healthy volunteers for 7 days the concentration of bosentan in the blood decreased by 58%, and in some patients - by 90 %.
As a result, a significant decrease in the effectiveness of Tracleer® can be expected when used together with rifampicin. The simultaneous use of rifampicin and Tracleer® is not recommended.
There is insufficient data on the combined use of bosentan with other CYP3A4 inducers, such as carbamazepine, phenobarbital, phenytoin and St. John's wort. However, a decrease in the systemic exposure of bosentan can be expected when used concomitantly. A significant decrease in the effectiveness of treatment cannot be ruled out.
Lopinavir/ritonavir (and other protease inhibitors whose effects are enhanced by ritonavir):
with simultaneous use of the drug Tracleer® at a dose of 125 mg 2 times / day and the combination of lopinavir + ritonavir 400 + 100 mg 2 times / day for 9.5 days in healthy volunteers, the minimum initial concentration of bosentan in the blood was approximately 48 times higher compared with the concentration when using bosentan alone. On day 9, the concentration of bosentan in the blood was 5 times higher than when taking bosentan alone. Inhibition by ritonavir of the CYP3A4 isoenzyme and the protein responsible for the transport of bosentan into hepatocytes leads to a decrease in the clearance of bosentan and likely underlies this interaction. In patients concomitantly taking bosentan and lopinavir + ritonavir or other protease inhibitors, the effect of which is enhanced by ritonavir, monitoring of the tolerability of Tracleer is necessary.
When used simultaneously with Tracleer® for 9.5 days, a clinically insignificant decrease in the concentration of lopinavir and ritonavir was observed (by approximately 14% and 17%, respectively). However, complete induction by bosentan may not have been achieved, so the possibility of a further decrease in protease inhibitor concentrations cannot be excluded. Appropriate monitoring of HIV therapy is recommended. Similar effects can be expected with the use of other protease inhibitors, the effect of which is enhanced by ritonavir (see section "Special instructions and precautions for use").
Other antiretroviral drugs:
Due to lack of data, specific recommendations for other antiretroviral drugs cannot be made.
Given the significant liver toxicity of nevirapine, which may enhance the hepatotoxicity of bosentan, the combined use of these drugs is not recommended.
Hormonal contraceptives:
with simultaneous use of Tracleer® for 7 days at a dose of 125 mg 2 times a day and one dose of an oral contraceptive containing 1 mg of norethisterone and 35 mcg of ethinyl estradiol, a decrease in the AUC of both components was observed (by 14% and 31%, respectively). In some patients, the reduction in exposure to norethisterone and ethinyl estradiol reached 56% and 66%, respectively. Thus, hormonal contraception alone, regardless of the route of administration (oral, injection, transdermal or implant), cannot be considered a reliable contraceptive.
Warfarin:
simultaneous use of the drug Traclear® at a dose of 500 mg 2 times a day for 6 days leads to a decrease in the blood concentration of both S-warfarin (substrate of the CYP2C9 isoenzyme) and R-warfarin (substrate of the CYP3A4 isoenzyme) by 29% and 38%, respectively. Experience with the simultaneous use of Tracleer® and warfarin in patients with PAH did not reveal clinically significant changes in the international normalized ratio (INR) or the dose of warfarin (initial dose compared with maintenance dose). In addition, the incidence of warfarin dose changes during studies due to INR fluctuations or ADRs did not differ between patients receiving bosentan or placebo. There is no need to change the dose of warfarin or other similar oral anticoagulants when adding Traclear® to therapy. However, more frequent monitoring of the INR is recommended, especially when starting to use Traclear® and when increasing its dose.
Simvastatin:
with simultaneous use of the drug Tracleer® at a dose of 125 mg 2 times / day for 5 days, the concentration of simvastatin (a substrate of the CYP3A4 isoenzyme) and its active metabolite beta-hydroxy acid is reduced in the blood by 34% and 46%, respectively. Concomitant use of simvastatin does not affect the concentration of bosentan in the blood. It is recommended to monitor the concentration of cholesterol in the blood and adjust the dose of simvastatin accordingly.
Ketoconazole:
simultaneous use of the drug Tracleer® at a dose of 62.5 mg 2 times a day for 6 days and ketoconazole, a powerful inhibitor of the CYP3A4 isoenzyme, is accompanied by a twofold increase in the concentration of bosentan in the blood.
There is no need to change the dose of Tracleer®. Although data from in vivo ,
it is assumed that similar increases in bosentan blood concentrations are expected with concomitant use of other strong CYP3A4 inhibitors, such as itraconazole and ritonavir. However, with simultaneous use of bosentan and an inhibitor of the CYP3A4 isoenzyme, in patients with reduced activity of the CYP2C9 isoenzyme, there is a risk of a more pronounced increase in the concentration of bosentan. which may contribute to the emergence of potentially dangerous ADRs.
Epoprostenol:
Limited results from a study (AC-052-356 [BREATHE-3]), in which 10 children received Tracleer® concomitantly with epoprostenol, indicate that after single and multiple doses, the C and AUC of bosentan were approximately the same in patients receiving and who did not receive epoprostenol infusion (see section “Pharmacological properties”).
Sildenafil:
with simultaneous use of Tracleer® at a dose of 125 mg 2 times / day (steady state) and sildenafil at a dose of 80 mg 3 times / day for 6 days in healthy volunteers, a decrease in the AUC of sildenafil by 63% and an increase in the AUC of bosentan by 50% were observed. . Caution should be exercised during simultaneous use.
Digoxin:
simultaneous use of Tracleer® at a dose of 500 mg 2 times a day for 7 days is accompanied by a decrease in AUC, Cmax and Cmax of digoxin by 12%, 9% and max min 23%, respectively. It is possible that the mechanism of this interaction is based on the induction of glycoprotein P. The clinical significance of this interaction is unlikely.
In children
Drug interaction studies have been conducted in adults only.
Tracleer DT dispersible tablets 32 mg No. 56
Action
Bosentan is a non-selective antagonist of endothelin receptors such as ETA and ETB.
Bosentan reduces both pulmonary and systemic vascular resistance, resulting in an increase in cardiac output without an increase in heart rate. The neurohormone endothelin-1 (ET-1) is one of the most powerful vasoconstrictors, which also has the ability to stimulate fibrosis, cell proliferation, hypertrophy and remodeling, and also exhibits pro-inflammatory activity. These effects are induced by ET-1 binding to ETA and ETB receptors located in the endothelium and vascular smooth muscle cells. The concentration of ET-1 in tissues and blood plasma increases in certain cardiovascular diseases and connective tissue pathologies, incl. in pulmonary arterial hypertension (PAH), scleroderma, acute and chronic heart failure, myocardial ischemia, arterial hypertension and atherosclerosis, which suggests the participation of ET-1 in the pathogenesis and development of these diseases. In PAH and heart failure, in the absence of ET receptor antagonism, an increase in ET-1 concentration strictly correlates with the severity and prognosis of these diseases.
Bosentan competes with ET-1 and other ET peptides for binding to ETA and ETB receptors, with a slightly higher affinity for ETA receptors (Ki = 4.1-43 nmol) compared to ETB receptors (Ki = 38-730 nmol).
Bosentan specifically blocks ET receptors and does not bind to other receptors.
When studying PAH in animal models, it was shown that long-term oral administration of bosentan reduces pulmonary vascular resistance and promotes the reverse development of vascular hypertrophy of the lungs and right ventricle. In pulmonary fibrosis, bosentan has been shown to reduce collagen accumulation in the lungs.
The results of invasive hemodynamic studies showed that treatment with bosentan leads to a significant increase in cardiac index, as well as a significant decrease in pulmonary artery pressure, pulmonary vascular resistance and mean right atrial pressure.
Long-term (for 12 and 16 weeks) treatment of adult patients with PAH (primary and secondary, mainly associated with scleroderma) FC III-IV according to WHO classification with bosentan in combination with anticoagulants, vasodilators (calcium channel blockers), diuretics, oxygen and digoxin, but not epoprostenol, was accompanied by a decrease in the severity of PAH symptoms and a significant increase in exercise tolerance (as measured by the 6-minute walk test). These effects were observed at 4 weeks, were evident at 8 weeks, and persisted for up to 28 weeks in the active treatment subgroup.
A study of patients with PAH class II showed a significant increase in the time to onset of clinical deterioration (a composite point including progression of disease symptoms, hospitalization due to PAH, and deaths).
In patients with PAH FC III and heart disease combined with hemodynamic abnormalities such as Eisenmenger syndrome, an increase in mean blood oxygen saturation indicated that bosentan did not worsen hypoxemia and that mean pulmonary vascular resistance was significantly reduced in the bosentan group.
When studying bosentan in patients with PAH III FC in combination with HIV infection, an increase in exercise tolerance was shown in comparison with baseline data.
In the two main placebo-controlled studies and their open-label extensions, all patients receiving bosentan had vital signs assessed over a long period of time. The average duration of bosentan use was 1.9 ± 0.7 years (range 0.1 to 3.3 years), and the clinical condition of patients was monitored for an average of 0.2 ± 0.6 years. In the majority of patients, the diagnosis of primary PAH was confirmed (72%) and FC III (84%) was determined according to the WHO classification. The survival rate in the group as a whole (as estimated by the Kaplan-Meier method) after 1 year of treatment with bosentan was 93%, and after 2 years it was 84%. Patients with systemic scleroderma had lower Kaplan-Meier survival rates.
Studies conducted in children with PAH
A study of the pharmacokinetic parameters of bosentan was carried out in children with PAH II-III FC aged from 3 to 15 years during 12 weeks of drug therapy. Analysis of hemodynamic parameters indicates an increase in cardiac index (CI) by 0.5 l/min/m2, as well as a moderate decrease in mean pulmonary artery pressure (PAP) to 8 mm Hg. and pulmonary vascular resistance (PVR) - up to 389 dyn-s/cm5.
Bosentan, in the dosage form of dispersible tablets, was used at a dose of 2 and 4 mg/kg body weight 2 times a day in 36 patients aged 2 to 11 years. The risk of worsening the disease (death, lung transplant, or hospitalization due to worsening PAH), estimated using the Kaplan-Meier method, was 78.9% after 2 years. The overall survival rate, as assessed by Kaplan-Meier, after 2 years was 91.2%.
A study of 64 children aged 3 months to 11 years with stable PAH who received bosentan 2 mg/kg body weight 2 or 3 times daily for 24 weeks found that the clinical condition of the majority of patients remained stable according to the FC (97% - when taking the drug 2 times/day, 100% - 3 times/day) and the results of the general clinical assessment of the researchers (94% - when taking the drug 2 times/day, 93% - 3 times/day). Uncomplicated PAH, as assessed by the Kaplan-Meier method (cases of death, lung transplantation, or hospitalization due to worsening PAH), was noted in 96.9% and 96.7% of patients taking the drug 2 and 3 times a day, respectively.
A clinically significant advantage of using the drug at a dose of 2 mg/kg body weight 3 times a day compared to taking it 2 times a day has not been established.
Studies conducted in newborns with persistent pulmonary hypertension of the newborn (PPHN)
In a double-blind, placebo-controlled, randomized trial in infants born preterm or normal (gestational age 36–42 weeks) with PPHN and a suboptimal response to inhaled nitric oxide (iNO) for at least 4 hours as an adjunctive treatment Bosentan was administered through a nasogastric tube in the dosage form of dispersible tablets at a dose of 2 mg/kg body weight 2 times a day (n=13) or placebo (n=8) at the time of maximum NO concentration in the blood plasma. Bosentan was administered until complete discontinuation of iNO or until treatment effect subsided (requirement for extracorporeal membrane oxygenation [ECMO] or alternative pulmonary nasodilation). The maximum duration of treatment was 14 days.
The mean duration of treatment was 4.5 days (range 0.5 to 10.0 days) in the bosentan group and 4.0 days (range 2.5 to 6.5 days) in the placebo group.
The results obtained in this population do not indicate additional benefits of bosentan:
- the average duration of use of iNO with simultaneous use of bosentan was 3.7 days and 2.9 days with placebo (p = 0.34);
- the average duration of stay on mechanical ventilation was 10.8 days with simultaneous use of bosentan and 8.6 days with placebo (p = 0.24);
- one patient receiving bosentan had no treatment effect (requirement for ECMO, according to protocol requirements), which was diagnosed based on an increase in the oxygenation index 8 hours after the first dose of the drug. The patient's condition improved during 60 days of follow-up.
Combined use with epoprostenol
The combined use of bosentan and epoprostenol was studied in two studies: 10 of 19 pediatric patients received both bosentan and epoprostenol for 12 weeks. The safety profile of the combination treatment did not differ from the safety profile when using the drugs separately; the combination treatment was well tolerated in children and adult patients. Clinical benefit of this combination treatment was not observed.
Systemic scleroderma with ulcerative lesions of the extremities
The results of two clinical studies in adult patients with systemic scleroderma and extremity ulcers (in the acute stage or in cases where the ulcer was noted within the last year) showed that during the entire period of use of bosentan there was a significant decrease in the number of new extremity ulcers compared with with placebo.
Patients receiving bosentan or placebo for 16 weeks experienced an average of 1.4 and 2.7 new ulcer lesions, respectively (p=0.0042). In the 24-week study, the number of new limb ulcers per patient averaged 1.9 and 2.7, respectively (p=0.0351). The effect of bosentan on the rate of healing of ulcerative lesions has not been established.
Pharmacokinetics
Pharmacokinetic parameters in healthy volunteers depend on the dose and timing of bosentan administration. After oral administration, systemic exposure of bosentan is proportional in doses up to 500 mg. When bosentan is administered orally at higher doses, plasma Cmax and AUC increase less proportionally to dose. Limited pharmacokinetic data suggest that bosentan exposure in adult patients with PAH is approximately 2-fold higher than in healthy volunteers.
Suction
After oral administration of the drug, Cmax in blood plasma is achieved within 3-5 hours. The absolute bioavailability of bosentan in healthy volunteers after oral administration is about 50% and does not depend on food intake.
Distribution
Bosentan is highly bound (more than 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate red blood cells. After a single intravenous injection at a dose of 250 mg, Vd is 18 l.
Metabolism and excretion
After a single intravenous administration of bosentan at a dose of 250 mg, its clearance is 8.2 l/h. T1/2 - 5.4 hours.
With repeated use, the concentration of bosentan in the blood plasma decreases gradually and is 50-65% of the concentration with a single use. An equilibrium state is achieved within 3-5 days.
Bosentan is metabolized in the liver with the participation of cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Bosentan is excreted through the intestines with bile, less than 3% of the oral dose is excreted by the kidneys.
During the metabolism of bosentan, 3 metabolites are formed, one of which has pharmacological activity. The pharmacologically active metabolite is predominantly excreted in bile. In adult patients, the concentration of the active metabolite in the blood plasma is higher than in healthy volunteers. In patients with signs of cholestasis, systemic exposure to this metabolite may be increased.
Bosentan is an inducer of the CYP2C9 and CYP3A4 isoenzymes, and possibly also the CYP2C19 isoenzyme and P-glycoprotein. In vitro, bosentan inhibits the activity of BSEP (bile salt excretion pump).
In vitro studies have shown that bosentan does not have a significant inhibitory effect on a number of CYP isoenzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, bosentan does not increase the plasma concentrations of drugs whose metabolism is mediated by these isoenzymes.
Comparison of dosage forms
A crossover study examined pharmacokinetic parameters in 16 healthy adult volunteers who took bosentan 62.5 mg film-coated tablets or 64 mg dispersible tablets (2 tablets of 32 mg). After taking dispersible tablets, the concentration of bosentan in the blood plasma was lower than after taking film-coated tablets (geometric mean ratio AUC0-∞ 0.87). The type of dosage form did not have a significant effect on Tmax and T1/2 of bosentan.
Pharmacokinetics in special groups of patients
Based on the results of studies, it is assumed that the pharmacokinetics of bosentan in adult patients is not significantly influenced by factors such as gender, body weight, race or age.
Children
Pharmacokinetic studies of bosentan have also been conducted in children. However, the pharmacokinetic characteristics of bosentan in children under 2 years of age have not been fully determined due to limited data in this category of patients.
The results of a pharmacokinetic study in 19 children with PAH aged 3 to 15 years with single and multiple oral doses of bosentan in the dosage form of film-coated tablets at a dose of 2 mg/kg body weight 2 times a day indicate that the exposure of bosentan decreases over time in full accordance with the autoinductive properties of bosentan. The mean AUC (CV%) values of bosentan in children receiving bosentan at doses of 31.25 mg, 62.5 mg, or 125 mg twice daily were 3.496 (49%), 5.228 (79%), and 6.124 (27%) ng×h/h. ml, respectively, and were below the average value of this indicator (8.149 (47%) ng×h/ml) in adult patients with PAH taking bosentan at a dose of 125 mg 2 times a day. At steady state, systemic exposure in children weighing 10-20 kg, 20-40 kg and more than 40 kg was, respectively, 43%, 67% and 75% of the corresponding values in adults.
A study of dispersible tablets in 36 patients with PAH aged 2 to 11 years did not reveal a proportional dependence of pharmacokinetic parameters on the dose, since at steady state the concentration of bosentan in the blood plasma and AUC values were similar when administered orally with bosentan at a dose of 2 mg/kg and 4 mg/kg body weight 2 times/day, respectively (AUCtt: 3.577 and 3.371 ng×h/ml). The total systemic exposure when taking bosentan at a dose of 125 mg 2 times a day in children was approximately 2 times lower than in adult patients, while in most cases the exposure rates in children and adults were the same.
Overall, in a group of children (n=31) who took bosentan at a dose of 2 mg/kg body weight 2 times a day, its average daily exposure was 8.535 ng×h/ml, and AUCtt was 4.268 ng×h/ml (CV : 61%). In children aged 3 months to 2 years, the average daily exposure was 7.879 ng×h/ml and AUCtt was 3.939 ng×h/ml (CV: 72%). In children from 3 months to 1 year (n=2) - AUCtt was 5.914 ng×h/ml (CV: 85%), and in patients from 1 year to 2 years (n=7) AUCtt - 3.507 ng×h/ ml (CV: 70%). In patients older than 2 years (n=22), the mean daily exposure to bosentan was 8.820 ng×h/ml and AUCtt was 4.410 ng×h/ml (CV: 58%). The use of bosentan at a dose of 2 mg/kg 3 times a day did not lead to an increase in bosentan plasma concentrations, and the average daily exposure was 7.275 ng×h/ml (CV: 83%, n=27).
The findings confirm that bosentan plasma concentrations reach a plateau in children when administered at lower doses compared to adults. In addition, taking the drug in doses above 2 mg/kg 2 times/day (4 mg/kg 2 times/day or 2 mg/kg 3 times/day) does not increase bosentan exposure in children.
In a study performed in neonates, bosentan concentrations increased slowly and continued to increase after the end of the first dose, demonstrating low exposure (AUC0-12 in whole blood 164 ng×h/mL, n=11). At steady state, the AUCtt was 6.165 ng×h/ml (CV: 133%, n=7), which is comparable to the exposure in adult patients with PAH when taking bosentan at a dose of 125 mg 2 times a day, taking into account the distribution ratio of the drug in the whole body blood and blood plasma equal to 0.6.
The significance of the data obtained regarding the hepatotoxicity of the drug has not been determined. The pharmacokinetics of bosentan are not significantly affected by gender and concomitant use of epoprostenol.
Liver dysfunction
In patients with mild liver failure (class A according to the Child-Pugh classification), no significant changes in the pharmacokinetics of the drug were observed. In these patients, the steady-state AUC of bosentan was 9% higher, and its active metabolite, Ro 48-5033, was 33% higher compared with that in healthy volunteers.
The effect of moderate hepatic impairment (Child-Pugh class B) on the pharmacokinetic parameters of bosentan and its main metabolite, Ro 48-5033, was studied in 5 patients with PAH due to portal hypertension and moderate hepatic impairment, as well as in 3 patients with PAH due to other causes and normal liver function. In patients with class B hepatic impairment, the mean steady-state AUC of bosentan was 360 (212-613) ng×h/ml, i.e. was 4.7 times higher, and the average AUC value of the active metabolite Ro 48-5033 was 106 (58.4-192) ng×h/ml, i.e. 12.4 times higher than in patients with normal liver function (bosentan: mean AUC: 76.1 [9.07-638] ng×h/ml; Ro 48-5033: mean AUC: 8.57 [1.28-57.2] ng×h/ml) . Despite the small number of patients and high variability in the data obtained, these results indicate a significant increase in systemic exposure to bosentan and its main metabolite Ro 48-5033 in patients with moderate hepatic impairment (Child-Pugh class B).
The pharmacokinetics of bosentan in patients with severe hepatic impairment (Child-Pugh class C) has not been studied. The use of Tracleer®DT is contraindicated in patients with moderate to severe hepatic impairment (class B or C according to the Child-Pugh classification).
Renal dysfunction
In patients with severe renal failure (creatinine clearance 15-30 ml/min), the plasma concentration of bosentan is reduced by approximately 10%. The concentration of bosentan metabolites in the blood plasma increases approximately 2-fold compared to patients with normal renal function. No dose adjustment is required in patients with renal failure. The use of bosentan during hemodialysis has not been studied. Given the physicochemical properties of bosentan and its high degree of binding to plasma proteins, significant removal of bosentan from the vascular bed during hemodialysis is not expected.
