The primary endpoint in each study was the change in distance walk test at 12 weeks in the first study and at the 16th – the second. Improved exercise tolerance was observed of therapy, it was evident at 8 weeks and persisted until 28 weeks of double-blind treatment in the subgroup of patients with the sample. In receiving treatment with bosentan decreased the severity of symptoms of exemestane pct. Also in this subgroup of patients noted improvement in dyspnea during walking tests.
In the first study showed that the use of bosentan is accompanied by an increase in cardiac index and is associated with significant reduction in pressure in the pulmonary artery, pulmonary vascular resistance and the average pressure in the right atrium. Application of research results of bosentan in patients (middle distance test with a 6-minute walk test – 435 m) for 6 months showed a decrease in the frequency of clinical deterioration in patients, and – reducing the number of deaths and hospitalizations . In connection with worsening in patients receiving bosentan, hospitalization marked 1, while in the group of patients not receiving bosentan – 3 cases. When viewed within 6 months registered 1 case of death in each group that does not allow to evaluate the effect of bosentan on survival. In patients with PAH FC III and Eisenmenger syndrome associated with congenital heart disease when used in doses of bosentan 62.5 mg 2 times / day. and 125 mg of 2 times / day.after 16 weeks of treatment, there were no deterioration hypoxemia (oxygen saturation in the blood plasma increased by 1%). Average vascular resistance in the pulmonary artery decreased significantly, improved exercise tolerance (the average distance test with a 6-minute walk test increased by 53 m).
In the bosentan study in patients with exemestane pct, associated infection, showed a significant increase in exercise tolerance .
Improved survival rates in the long-term period was observed in all patients treated with bosentan in the two placebo-controlled studies and their extensions. The average duration of use of bosentan was 1,9 ± 0,7 years (from 0.1 years to 3.3 years), the observation was carried out for 2,0 ± 0,6 years. Most of the patients with confirmed diagnosis of primary . Overall survival in the general population through the use of bosentan 1 year is 93%, and after 2 years – 84% . Survival in patients with primary exemestane pct after 1 and 2 years was higher than – 96% and 89%. respectively. According to a comparative study in 6 specialized centers (682 patients) survival in patients with primary PAH receiving bosentan was comparable with those of epoprostenol.
In patients with systemic sclerosis evaluation of survival by the Kaplan-Meier was lower.
Efficacy in children with PAH
Parameter estimation of pharmacokinetics in children was performed during 12 weeks of bosentan.
The analysis of hemodynamic parameters indicates an increase in cardiac index 2 , as well as a decrease in pressure in the pulmonary artery . and pulmonary vascular resistance .
Systemic scleroderma with ulcerative lesions of the limbs
results of two clinical studies in adult patients with systemic sclerosis and ulcerative limb lesions (in the acute phase, or in cases where the canker observed during the last year) showed that the use of bosentan is accompanied by a significant decrease in the number of new ulcers limb lesions ., compared with placebo for the treatment period
in the 16 weeks study in patients receiving bosentan, on average 1.4 mentioned case of new ulcers, and patients receiving placebo – 2,7 cases (p = 0.0042). In another study, lasting 24 weeks, new ulcerative lesions of the limbs are noted in 1.9 and 2.7 cases, respectively (p = 0.0351). Effect exemestane pct of bosentan on the rate of healing of ulcerative lesions not found.
The pharmacokinetics of bosentan have studied in detail in healthy volunteers studies. Data for the study of the pharmacokinetics in a limited number of patients with PAH indicate that systemic exposure to bosentan in patients 2 times higher than in healthy volunteers.
The pharmacokinetic parameters in healthy volunteers dependent on dose and time of ingestion. After intravenous administration of bosentan volume of its distribution and clearance decreased with increasing dose and increased – eventually. After oral systemic exposure bosentan proportional at doses up to 500 mg. The ingestion of a higher dose of bosentan increase in maximum plasma concentration (area under “concentration-time” curve) with respect to disproportionate to the dose and a lower speed is achieved.