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Mechanism Of action
Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown.
Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease.
After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life (t½) is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about 2-fold greater in adult patients with pulmonary arterial hypertension than in healthy adult subjects.
Absorption and Distribution
The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food. The volume of distribution is about 18 L. Bosentan is highly bound ( > 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.
Metabolism and Elimination
Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10%–20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Total clearance after a single intravenous dose is about 4 L/hr in patients with pulmonary arterial hypertension. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine.
It is not known whether bosentan's pharmacokinetics is influenced by gender, race, or age.
In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure of bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan was not altered in patients with mild hepatic impairment.
In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and pulmonary arterial hypertension associated with portal hypertension than in 3 patients with normal liver function and pulmonary arterial hypertension of other etiologies.
The pharmacokinetics of Tracleer has not been evaluated in patients with severe liver impairment (Child- Pugh Class C) [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Use in Specific Populations].
In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to people with normal renal function. These differences do not appear to be clinically important.
Reproductive and Developmental Toxicology
Bosentan was teratogenic in rats given oral doses ≥ 60 mg/kg/day. In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day. Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that embryo-fetal toxicity is a class effect of these drugs.
Pulmonary Arterial Hypertension
WHO Functional Class III-IV
Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg twice daily and 250 mg twice daily) of Tracleer with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (WHO functional Class III–IV) pulmonary arterial hypertension: idiopathic or heritable pulmonary arterial hypertension (72%) or pulmonary arterial hypertension associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with pulmonary arterial hypertension associated with other conditions such as HIV disease or recurrent pulmonary emboli.
In both studies, Tracleer or placebo was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. Tracleer was given at a dose of 62.5 mg twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351.
The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years.
Submaximal Exercise Ability
Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 3.
Table 3: Effects of Tracleer on 6-minute walk distance
|Tracleer 125 mg twice daily
(n = 74)
|Tracleer 250 mg twice daily
(n = 70)
(n = 69)
|Tracleer 125 mg twice daily
(n = 21)
(n = 11)
|Baseline||326 ± 73||333 ± 75||344 ± 76||360 ± 86||355 ± 82|
|End point||353±115||379±101||336±129||431 ± 66||350±147|
|Change from baseline||27 ± 75||46 ± 62||-8 ± 96||70 ± 56||-6 ± 121|
|Placebo -subtracted||35 a||54b||76c|
|Distance in meters: mean ± standard deviation. Changes
are to week 16 for BREATHE-1 and to week 12 for Study 351.
ap=0.01; by Wilcoxon;
bp=0.0001; by Wilcoxon;
cp=0.02; by Student's t-test.
In both trials, treatment with Tracleer resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 1). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended [see DOSAGE AND ADMINISTRATION]. There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences.
Figure 1: Mean Change in 6min Walk Distance
Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined Tracleer (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean ± standard error of the mean.
Invasive hemodynamic parameters were assessed in Study 351. Treatment with Tracleer led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 4).
The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown.
Table 4: Change from Baseline to Week 12: Hemodynamic
|Tracleer 125 mg twice daily||Placebo|
|Mean CI (L/min/m²)||n=20||n=10|
|Baseline||2.35 ± 0.73||2.48 ± 1.03|
|Absolute Change||0.50 ± 0.46||-0.52 ± 0.48|
|Mean PAP (mmHg)||n=20||n=10|
|Baseline||53.7 ± 13.4||55.7 ± 10.5|
|Absolute Change||-1.6 ± 5.1||5.1 ± 8.8|
|Mean PVR (dyn•sec•cm-5)||n=19||n=10|
|Baseline||896 ± 425||942 ± 430|
|Absolute Change||-223 ± 245||191 ± 235|
|Mean RAP (mmHg)||n=19||n=10|
|Baseline||9.7 ± 5.6||9.9 ± 4.1|
|Absolute Change||-1.3 ± 4.1||4.9 ± 4.6|
|Values shown are means ± SD
ap ≤ 0.001; (b)p < 0.02
Symptoms and Functional Status
Symptoms of pulmonary arterial hypertension were assessed by Borg dyspnea score, WHO functional class, and rate of “clinical worsening.” Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in Tracleer-treated patients. There was a significant reduction in the rate of clinical worsening (Table 5 and Figure 2). Figure 2 shows the log-rank test reflecting clinical worsening over 28 weeks.
Table 5: Incidence of Clinical Worsening, Intent To
|Tracleer 125/250 mg twice daily
(n = 144)
(n = 69)
|Tracleer 125 mg twice daily
(n = 21)
(n = 11)
|Patients with clinical worsening||9 (6%)a||14 (20%)||0 (0%)b||3 (27%)|
|Death||1 (1%)||2 (3%)||0 (0%)||0 (0%)|
|Hospitalization for PAH||6 (4%)||9 (13%)||0 (0%)||3 (27%)|
|Discontinuation due to worsening of PAH||5 (3%)||6 (9%)||0 (0%)||3 (27%)|
|Receipt of epoprostenolc||4 (3%)||3 (4%)||0 (0%)||3 (27%)|
|Note: Patients may have had more than one reason for
ap=0.0015 vs. placebo by log-rank test. There was no relevant difference between the 125 mg and 250 mg twice daily groups.
bp=0.033 vs. placebo by Fisher's exact test.
cReceipt of epoprostenol was always a consequence of clinical worsening.
Figure 2: Time to Clinical Worsening (BREATHE -1)
Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (n=144 in the
Tracleer group and n=69 in the placebo group) participated in the first 16 weeks of the study. A subset of this population (n=35 in the Tracleer group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks.
WHO Functional Class II
In a randomized, double-blind, multicenter, placebo-controlled trial, 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received Tracleer 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or placebo (n = 92) for 6 months. Enrolled patients were treatment-na´ve (n = 156) or on a stable dose of sildenafil (n = 29). The coprimary endpoints were change from baseline to month 6 in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO functional class and hemodynamics were assessed as secondary endpoints.
Compared with placebo, Tracleer treatment was associated with a reduced incidence of worsening of at least one functional class (3% Tracleer vs. 13% placebo, p = 0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO2; p < 0.05). The + 19 m mean (+14 m median) increase in 6- minute walk distance with Tracleer vs. placebo was not significant (p = 0.08). There was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with Tracleer compared with placebo (hazard ratio 0.2, p = 0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline.
Long-term Treatment of PAH
Long-term follow-up of patients with Class III and IV PAH who were treated with Tracleer in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment.
These uncontrolled observations do not allow comparison with a group not given Tracleer and cannot be used to determine the long-term effect of Tracleer on mortality.
Pulmonary Arterial Hypertension related to Congenital Heart Disease with Left-to-Right Shunts
A small study (N=54) and its open label extension (N=37) of up to 40 weeks with patients with Eisenmenger physiology demonstrated effects of Tracleer on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).
Lack Of Benefit In Congestive Heart Failure
Tracleer is not effective in the treatment of congestive heart failure with left ventricular dysfunction. In a pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction < 35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or Tracleer (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. Use of Tracleer was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first 4 to 8 weeks after Tracleer was initiated. In a placebocontrolled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks of treatment with Tracleer. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
Last reviewed on RxList: 1/19/2016
This monograph has been modified to include the generic and brand name in many instances.
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