Treatment of pulmonary arterial hypertension with bosentan: from pathophysiology to clinical evidence

In addition to its potent vasoconstricting effect, endothelin (ET)-1 induces proliferation of pulmonary vascular cells and appears to play a pathogenic role in the development of pulmonary arterial hypertension (PAH). Blockade of the ET receptors has been proposed for the treatment of this condition. Bosentan (Tracleer^®, Actelion Pharmaceuticals), an oral ET_A/ET_B receptor antagonist, has been shown to improve exercise capacity, quality of life, haemodynamics and time to clinical worsening of patients with PAH in short-term placebo-controlled trials. These improvements were sustained, and a long-term observational study on idiopathic PAH patients suggested a favourable effect on survival in this subset. In the present report, the pharmacology, clinical efficacy and safety profile of bosentan are summarised. The place of bosentan among the current therapies available for the treatment of PAH is also discussed.     

Long-term trial of bosentan monotherapy for pulmonary arterial hypertension in Japanese patients

ABSTRACT

Objective: To determine the efficacy and safety of long-term bosentan monotherapy in Japanese patients with pulmonary arterial hypertension (PAH).

Research design and methods: The present study was an extension to a 12?week open-label trial of bosentan in which 21 Japanese patients with PAH received bosentan, 125?mg twice daily. Of the 21 patients in the initial trial, 20 elected to participate in the long-term study and to continue to receive bosentan for up to 3 years.

Main outcome measures: The primary efficacy measure was comparison of World Health Organization (WHO) functional class for pulmonary arterial hypertension following long-term (> 2.5 years) therapy compared with baseline (prior to initiation of bosentan). Secondary outcomes included time from initiation of bosentan therapy to clinical worsening and safety assessments.

Results: Bosentan treatment was continued for a median of 2.7 years (range 0.4–3.0 years); 12 patients received bosentan monotherapy for at least 2.5 years. Following long-term treatment, improvement of WHO functional class compared with baseline was observed in 9/12 patients (75.0%) and in 3/12 patients (25.0%) the functional class remained stable; no patient experienced a worsening of WHO functional class compared with baseline. Overall, long-term treatment with bosentan was well tolerated.

Conclusions: Long-term treatment with bosentan is well tolerated and is associated with sustained clinical improvement in Japanese patients with PAH. Bosentan, therefore, represents a valuable treatment option for Japanese patients with this devastating disease.     

Bosentan: a dual endothelin receptor antagonist

The peptide endothelin plays a significant role in a wide array of pathological conditions, including primary pulmonary hypertension and pulmonary arterial hypertension associated with collagen vascular disease. These are life-threatening conditions that can severely compromise the function of the lungs and heart. Inhibiting the actions of endothelin by blockade of its receptors provides a new and effective approach to therapy for patients with these conditions. Bosentan (Tracleer ) is the first orally-active dual endothelin receptor antagonist and has recently been approved in the US, Canada, Switzerland and the EU for the treatment of pulmonary arterial hypertension. Bosentan significantly improves exercise capacity, symptoms and functional status in patients with this disease and also slows clinical deterioration, which may be indicative of a delay of disease progression. Results from large-scale studies of bosentan in patients with pulmonary arterial hypertension and chronic heart failure have established its long-term safety and tolerability profiles. The introduction of the dual endothelin receptor antagonist bosentan has provided an essential treatment for pulmonary arterial hypertension and ongoing trials are evaluating its potential role in the management of other endothelin-mediated disease states.     

Bosentan

Importance to the field: Pulmonary arterial hypertension (PAH) is a morbid condition with high mortality if left untreated. Bosentan is an effective treatment option for group 1 pulmonary arterial hypertension. Bosentan improves exercise tolerance and functional class and delays the time to clinical worsening in these patients. Investigation is ongoing to determine its efficacy in other groups of pulmonary hypertension.

Areas covered in this review: This review provides a background on endothelin activity in PAH, as a rationale for the use of bosentan in this disease. It also presents evidence from key clinical trials of bosentan and discusses future directions in the study of bosentan to help the clinician better understand the role of bosentan in PAH management.

What the reader will gain: i) An understanding of the rationale for using endothelin receptor antagonists in treating PAH; ii) an understanding of the clinical evidence to support bosentan for the treatment of PAH; and iii) an understanding of how to use bosentan optimally in the treatment of PAH.

Take home message: Bosentan is an effective and safe treatment for patients with PAH. Patients with suspected PAH should be evaluated carefully as the use of bosentan in non-group 1 pulmonary hypertension is still being investigated. Patients on bosentan should be monitored with monthly liver transaminase testing. Coadministration with other drugs should be reviewed carefully as drug–drug interactions may be important.     

Bosentan

Bosentan (Tracleer), an orally administered dual endothelin (ET)(A) and ET(B) receptor antagonist, is indicated in the treatment of pulmonary arterial hypertension (PAH).The efficacy of oral bosentan 125 mg twice daily in improving exercise capacity has been demonstrated in well designed trials in adult patients with idiopathic PAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts, and in other trials in patients with idiopathic PAH or PAH associated with congenital heart disease or HIV infection. The beneficial effects of first-line bosentan treatment may be maintained for up to 1 year in patients with idiopathic PAH or PAH associated with connective tissue disease. Despite the potential for treatment-related teratogenicity and hepatotoxicity, long-term data indicate that bosentan is generally well tolerated at the approved dosages. Although well designed trials are required to establish the efficacy of bosentan versus or in combination with other specific PAH therapies, especially sildenafil, the convenient oral administration and lack of serious injection-related adverse effects may render bosentan preferable to other PAH therapies. Preliminary data indicate that bosentan may be effective in pediatric PAH patients, although randomized trials are required. Furthermore, bosentan may be a useful option for the prevention of digital ulcer development in patients with systemic sclerosis. Thus, in accordance with current clinical guidelines, bosentan is a convenient, effective, and generally well tolerated agent for use in the first-line treatment of class III PAH or second-line treatment of class IV PAH.     

A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension

The approval of macitentan has increased the number of pharmacological treatments of pulmonary arterial hypertension (PAH). Here, we review the effect on PAH of macitentan compared to other endothelin receptor antagonists. Drugs targeting the endothelin (ET) pathway include the selective ET_A receptor antagonist ambrisentan, the ET_A/ET_B receptor antagonists, bosentan and macitentan, which were recently approved for PAH treatment. Macitentan exhibits higher antagonistic potency than bosentan and ambrisentan in pulmonary smooth muscle cells. Compared to ambrisentan and bosentan, macitentan has a longer duration of action, reflected by the longer half‐life, as well as pharmacodynamics attributed to its active metabolite, ACT‐132577. The efficacy of macitentan on PAH was investigated in the phase III SERAPHIN trial (NCT00660179). Macitentan significantly reduced morbidity and mortality. It improved the 6‐min. walk distance (6MWD) among PAH patients. In the AMB‐320/321‐E (NCT00578786) study, ambrisentan improved exercise capacity. In the EARLY study (NCT00091715), bosentan showed improvements in 6MWD which were not statistically significant. Bosentan had an effect on PAH in patients with Eisenmenger syndrome (ES) in the BREATHE‐5 study (NCT00367770), while macitentan did not improve 6MWD in these patients, but there are differences regarding study size and functional class, and that 30% of the patients treated with macitentan were already in treatment with a phosphodiesterase type 5 inhibitor. Macitentan revealed a lower risk of developing peripheral oedema and hepatotoxicity in the SERAPHIN study. In summary, macitentan has an efficiency comparable to bosentan and ambrisentan in the treatment of PAH. Patients treated with macitentan exhibited less adverse effects compared to bosentan and ambrisentan. In patients with PAH associated with ES, the trials with bosentan and macitentan do not seem comparable, and it needs to be clarified whether these drugs are effective when administered as part of a combination treatment in this condition.     

Macitentan (Opsumit) for the treatment of pulmonary arterial hypertension

The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension (PAH). Antagonism of this pathway is recommended as initial therapy in low-risk patient with PAH to inhibit fibrosis, cell proliferation, and inflammation caused by endothelin. Prior to October 2013, ambrisentan, a selective ET_A receptor antagonist and bosentan, a dual ET_A/ET_B antagonist, were the only currently available agents for PAH targeting the endothelin pathway. Based on the results of the SERAPHIN trial, macitentan (brand name Opsumit^®), a new ET_A/ET_B antagonist, has been US FDA approved to delay disease progression and reduce hospitalizations for PAH. SERAPHIN is the first ERA trial to use an event-driven strategy with a composite primary end point of morbidity or mortality. Previous trials have focused on short-term outcomes, such as improved 6-min walk distance and WHO functional class.     

The pharmacology of bosentan

This article describes the pharmacological properties and the overall preclinical and clinical profiling of bosentan (Ro 47-0203), a non-peptide endothelin receptor antagonist with oral activity. Bosentan is a combined and competitive antagonist of both ET_A and ET_B receptors that is selective for the endothelin system. In vitro and in vivo, bosentan potently antagonises the vascular response elicited by the endothelins. Preclinical efficacy is demonstrated in a variety of pathological models including pulmonary and essential hypertension, renal failure of ischaemic and nephrotic origin and cerebral vasospasm following subarachnoid haemorrhage. Effects are particularly marked in experimental models of heart failure (HF) where bosentan acts as a potent vasodilator that improves overall left ventricular performance. After chronic treatment, bosentan also improves survival in rats with HF. As a result of the first encouraging clinical results that show pulmonary and systemic vasodilation, long-term studies are ongoing in the treatment of congestive heart failure (CHF).     

Treatment of pulmonary arterial hypertension with bosentan: from pathophysiology to clinical evidence

In addition to its potent vasoconstricting effect, endothelin (ET)-1 induces proliferation of pulmonary vascular cells and appears to play a pathogenic role in the development of pulmonary arterial hypertension (PAH). Blockade of the ET receptors has been proposed for the treatment of this condition. Bosentan (Tracleer, Actelion Pharmaceuticals), an oral ETA/ETB receptor antagonist, has been shown to improve exercise capacity, quality of life, haemodynamics and time to clinical worsening of patients with PAH in short-term placebo-controlled trials. These improvements were sustained, and a long-term observational study on idiopathic PAH patients suggested a favourable effect on survival in this subset. In the present report, the pharmacology, clinical efficacy and safety profile of bosentan are summarised. The place of bosentan among the current therapies available for the treatment of PAH is also discussed.     

The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET_B) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ET_A) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ET_A receptor antagonism may have a role in the treatment of atherosclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ET_A receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the non-selective ET or selective ET_A receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.     

Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension

AIMS: To determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension. METHODS: Ten patients (aged 39-77 years) with pulmonary arterial hypertension in WHO functional class III received bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily for a second month. Sildenafil 100 mg was given as a single dose before starting bosentan (visit 1) and at the end of each month of bosentan treatment (visits 2 and 3). Sildenafil and its primary metabolite, desmethylsildenafil, were measured in plasma at 0 h and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h using liquid chromatography-tandem mass spectrometry. Statistical analysis was by repeated measures anova, using log transformed data where appropriate. RESULTS: Treatment with bosentan 62.5 mg twice daily for 4 weeks was associated with a two-fold increase in sildenafil clearance/F and a 50% decrease in the AUC (P < 0.001). Increasing the dose of bosentan to 125 mg twice daily led to a further increase in sildenafil oral clearance and decrease in the AUC (P < 0.001 vs. 62.5 mg bosentan). The ratio of AUC on bosentan treatment relative to that of visit 1 was 0.47 [95% confidence interval (CI) 0.36, 0.61] for visit 2 and 0.31 (95% CI 0.23, 0.41) for visit 3 (P < 0.001). Sildenafil C(max) fell from 759 ng ml(-1) on visit 1 to 333 ng ml(-1) on visit 3 (P < 0.01) and there was a significant decrease in the plasma half-life of sildenafil on the higher bosentan dose (P < 0.05). The AUC and plasma half-life of desmethylsildenafil was also decreased by bosentan in a dose-dependent manner (P < 0.01). CONCLUSIONS: Bosentan significantly decreases the plasma concentration of sildenafil when coadministered to patients with pulmonary hypertension.     

Ambrisentan,an endothelin receptor type A-selective endothelin receptor antagonist,for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ET_A-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential.     

Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil

Objective

The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH).

Methods

A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1–6 and 11–16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7–17.

Results

On Day 16, bosentan decreased the maximum plasma concentration of sildenafil ©_max) by 55.4% [90% confidence interval (CI) 40.3–66.6%] and the area under the plasma concentration versus time curve over a dosing interval $ {\left( {{\text{AUC}}_{\tau } } \right)} Objective The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH). Methods A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1–6 and 11–16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7–17. Results On Day 16, bosentan decreased the maximum plasma concentration of sildenafil ?_max) by 55.4% [90% confidence interval (CI) 40.3–66.6%] and the area under the plasma concentration versus time curve over a dosing interval by 62.6% (90% CI 56.8–67.7%). Sildenafil increased bosentan C_max by 42.0% (90% CI 15.4–74.8%) and by 49.8% (90% CI 28.7–74.5%). Bosentan and sildenafil in combination were well tolerated, with no serious adverse events reported. All adverse events were of mild or moderate intensity. Conclusions In healthy volunteers, there is a mutual pharmacokinetic interaction between bosentan and sildenafil that may influence the dosage of each drug in a combination treatment. The clinical implications of combination therapy with bosentan and sildenafil are as yet unknown, and further trials in patients with PAH are needed.     

Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects

Tadalafil, an oral phosphodiesterase 5 (PDE5) inhibitor, is being investigated as a treatment for pulmonary arterial hypertension. Bosentan is an oral endothelin receptor antagonist widely used in the treatment of pulmonary arterial hypertension. Tadalafil is mainly metabolized by cytochrome P450 (CYP) 3A4, and as bosentan induces CYP2C9 and CYP3A4, a pharmacokinetic interaction is possible between these agents. This open-label, randomized study investigated whether any pharmacokinetic interaction exists between tadalafil and bosentan. Healthy adult men (n = 15; 19-52 years of age) received 10 consecutive days of tadalafil 40 mg once daily, bosentan 125 mg twice daily, and a combination of both in a 3-period, crossover design. Following 10 days of multiple-dose coadministration of bosentan and tadalafil, compared with tadalafil alone, tadalafil geometric mean ratios (90% confidence interval [CI]) for AUCtau and Cmax were 0.59 (0.55, 0.62) and 0.73 (0.68, 0.79), respectively, with no observed change in tmax. Following coadministration of bosentan with tadalafil, bosentan ratios (90% CI) for AUCtau and Cmax were 1.13 (1.02, 1.24) and 1.20 (1.05, 1.36), respectively. Tadalafil alone and combined with bosentan was generally well tolerated. In conclusion, after 10 days of coadministration, bosentan decreased tadalafil exposure by 41.5% with minimal and clinically irrelevant differences (<20%) in bosentan exposure.     

Bosentan: new preparation. Pulmonary hypertension: an option before epoprostenol infusion

(1) Pulmonary hypertension is a progressive disorder characterised by abnormally high pulmonary artery pressure, leading to right ventricular failure and death, generally after a few years. (2) Treatment usually combines an anticoagulant, oxygen therapy, a diuretic and, sometimes a calcium channel blocker. Efficacy is poorly documented but appears to be limited. Long-term treatment with epoprostenol (prostacyclin), given as a continuous intravenous infusion via a central catheter and pump improves the quality of life of patients with severe pulmonary hypertension (NYHA classes III and IV, associated with discomfort during daily activities or even at rest). The impact of this treatment on survival seems to depend on the type of pulmonary hypertension: benefits were seen in a trial in patients with idiopathic pulmonary hypertension, while there was no effect in another trial in patients with pulmonary hypertension associated with scleroderma. Epoprostenol causes numerous adverse effects, some of which can be severe. (3) Marketing authorisation was recently granted in Europe for oral bosentan therapy for pulmonary arterial hypertension severe enough to restrict daily activities. (4) Two placebo-controlled trials lasting 12 to 16 weeks included 32 and 213 patients who responded inadequately to calcium channel blockers. They showed that the 6-minute walking distance improved by a median of 76 metres and 44 metres, respectively. In the trial with 213 patients, 42% of patients in the bosentan group and 30% of those in the placebo group were improved according to the NHYA scale. No impact on survival was observed in these short trials. (5) A trial in 33 patients showed no difference in symptom improvement between groups treated with intravenous epoprostenol + oral bosentan or intravenous epoprostenol + oral placebo. (6) Two adverse effects require monitoring, namely anemia and elevated transaminase activity. Bosentan carries a risk of multiple pharmacokinetic interactions and is teratogenic in animals. Women taking bosentan cannot use hormone-based contraception, because of a pharmacokinetic interaction. (7) In practice, oral bosentan improves symptoms in patients whose daily activities are restricted by pulmonary arterial hypertension. Bosentan is easy to use, making it an option before continuous intravenous epoprostenol infusion, even though it may not be as effective.     

Ambrisentan

Elevated endothelin (ET)-1 levels are strongly correlated with the pathogenesis and prognosis of pulmonary arterial hypertension (PAH). Ambrisentan is an orally active, highly selective ETA receptor antagonist with >4000-fold higher selectivity over the ETB receptor. In two large, well designed, 12-week, placebo-controlled, phase III trials (ARIES-1, n = 202 and ARIES-2, n = 192) in patients with PAH (WHO group I), ambrisentan 2.5-10 mg once daily significantly increased 6-minute walk distance by 31-59 m from baseline (primary outcome measure) versus placebo. The incidence of clinical worsening (secondary outcome measure) was significantly delayed for the combined ambrisentan 5 mg once daily groups versus the combined placebo groups from ARIES-1 and -2. At week 12, WHO functional class distribution was significantly improved with once-daily ambrisentan 5 mg, and Borg dyspnoea scores were significantly improved with ambrisentan 2.5-10 mg versus placebo in combined data from the ARIES-1 and -2 trials. The beneficial effects of ambrisentan on exercise capacity, WHO functional class and Borg dyspnoea scores seen at 12 weeks were maintained at 48 weeks in the ARIES-E phase III extension trial (n = 361). One-year survival rates with ambrisentan were 95-97%. Treatment with ambrisentan for up to 2.8 years was generally well tolerated in clinical trials.     

Bosentan for pulmonary arterial hypertension

Pulmonary arterial hypertension is an uncommon but disabling and often fatal condition, in which there is a sustained rise in pulmonary arterial pressure due to progressive obliteration of the pulmonary vascular bed. [symbol: see text] Bosentan (Tracleer-Actelion), which belongs to a new class of drugs called endothelin receptor antagonists, is now available for treating patients with pulmonary arterial hypertension. Here we assess whether bosentan offers worthwhile benefits in the management of patients with this condition.     

Sitaxsentan in the management of pulmonary arterial hypertension.

PURPOSE: The pharmacology, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosing and administration of the endothelin receptor antagonist, sitaxsentan, and its role in the treatment of pulmonary arterial hypertension (PAH) are reviewed. SUMMARY: PAH is a serious and potentially devastating chronic disorder of the pulmonary circulation. Bosentan is the first and only approved endothelin receptor antagonist for the treatment of PAH. Endothelin-1, a potent endogenous vasoconstrictor and smooth-muscle mitogen, has been shown to be overexpressed in the plasma and lung tissue of patients with PAH; the reduction or blockade of entothelin-1 may aid in disease symptomatology and progression. Activation of ET(A) leads to vasoconstriction and vascular smooth-muscle-cell proliferation. Sitaxsentan is an orally active, organic nonpeptide that binds competitively to the ET(A) receptor. Sitaxsentan, unlike bosentan, has a high affinity for the ET(A) receptor. In one trial, sitaxsentan was compared with placebo, and the results suggested that sitaxsentan was more effective than placebo. A 12-week, open-label trial demonstrated the safety and efficacy of sitaxsentan in 20 patients. The Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) trial randomized patients to receive placebo, sitaxsentan 100 mg orally once daily, or sitaxsentan 300 mg orally once daily. Significant improvements in exercise capacity and cardiopulmonary hemodynamics were demonstrated. The results of STRIDE-2, the second randomized sitaxsentan trial, demonstrated the efficacy and safety of 100 mg sitaxsentan and the unacceptable safety profile of 300 mg sitaxsentan. CONCLUSION: Sitaxsentan is an orally administered endothelin receptor blocker that offers the effective and safe treatment of patients with mild to moderate PAH.     

Bosentan in systemic sclerosis

Systemic sclerosis (SSc) is a relatively rare chronic connective tissue disease characterized by varying degrees of skin fibrosis and visceral organ involvement. Pulmonary compromise, including pulmonary arterial hypertension and interstitial lung disease, is currently the leading cause of death in patients with SSc. Digital ulcers are common complications which lead to substantial morbidity and functional limitation. Until recently, treatment options for these complications were quite limited. Endothelin-1 (ET-1) is a peptide that has a role in promoting both vascular injury and the fibrotic process in SSc. Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. In patients with pulmonary hypertension secondary to SSc, bosentan therapy prevents deterioration in exercise capacity and may improve survival. No beneficial effect was found in one study in patients with interstitial lung disease and SSc. Bosentan is able to reduce the number of new digital ulcers in patients with either a history of previous ulcers or an active ulcer, without expediting the healing of existing ulcers. Bosentan therapy is contraindicated in pregnancy and causes elevated liver transaminases in up to 14% of patients. Hence, monthly pregnancy tests should be performed and hepatic function should be monitored.     

Comparative investigation of the pharmacokinetics of bosentan in Caucasian and Japanese healthy subjects

Bosentan is a dual endothelin receptor antagonist in development for the treatment of pulmonary arterial hypertension in Japan, whereas it is registered for this indication in Europe and the United States. The present study was conducted to compare the pharmacokinetics of bosentan in Caucasian and Japanese subjects. In a double-blind, placebo-controlled, ascending single-dose, 5-way crossover study, 10 healthy Caucasian and 10 Japanese subjects (1:1 male/female ratio) received single doses of 31.25, 62.5, 125, and 250 mg of bosentan or placebo. Pharmacokinetic profiles of bosentan and its pharmacologically active hydroxy metabolite, Ro 48-5033, were determined after each dose of bosentan. The pharmacokinetics of bosentan were similar and dose proportional in both ethnic groups. However, peak plasma concentration values of Ro 48-5033 were significantly greater in Japanese subjects (P < .05). This difference could not be explained by the lower body weight of the Japanese subjects. Females in both groups tended to have higher exposure to both bosentan and Ro 48-5033 than males. The results suggest that, based on pharmacokinetic grounds, no dose adjustment of bosentan is necessary when used to treat Japanese patients in comparison to Caucasian patients.