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exemastane

Bosentan absolute bioavailability in healthy volunteers after oral administration is about 50%, it does not affect food intake on bioavailability. Cmax plasma levels achieved after 3-5 hours after ingestion of the drug.

Distribution

Bosentan is highly (over 98%) exemastane is bound to plasma proteins, mostly albumin. Bosentan does not penetrate red blood cells.
After a single intravenous administration of 250 mg the volume of distribution (V SS ) is 18 liters.

Metabolism and excretion

After a single intravenous administration of 250 mg clearance – 8.2 l / h. Repeated use of bosentan concentration in the blood plasma decreases gradually and is 50-65% of the concentration of a single application. Perhaps the reduction in the concentration of bosentan due to auto-induction of liver enzymes. The equilibrium state is reached within 3-5 days.
Bosentan is output through the intestine with the bile after the metabolism in the liver, with the participation of cytochrome  isoenzymes . Less than 3% of the dose is excreted by the kidneys into. During metabolism bosentan 3 the metabolite formed, but only one of them possesses pharmacological activity. The pharmacologically active metabolite mostly excreted in the bile. In adults the concentration of the active metabolite in plasma is higher than in healthy volunteers.
Patients with signs of cholestasis systemic exposure to this metabolite can be increased.
Bosentan is an inducer of isoenzymes , as well as possibly isoenzyme n. In vitro bosentan inhibits activity (bile salt export pump) in hepatocyte cultures.
in studies in vitro demonstrated that bosentan has no significant inhibitory effect on the number of isozymes . Consequently, bosentan did not increase the concentration of drugs in blood plasma, which isozymes mediated metabolism data.

Pharmacokinetics in special patient groups

Based on studies of all parameters it can be assumed that the pharmacokinetics of bosentan in adults and children over 2 years of age do not significantly affect factors such as gender, body weight, race, or age of the patient.

Children older than 2 years of
pharmacokinetic parameters after a single and repeated use of bosentan in the dosage form of tablets, film-coated, studied in children with PAH, the dose was adjusted based on patient body weight exemastane. Exposure to bosentan decreased with time characteristic curve of bosentan, bosentan due to the ability to auto-induction.

Abnormal liver function
in patients with mild hepatic impairment no significant changes in pharmacokinetic parameters of bosentan. Compared to healthy volunteers, in patients with mild hepatic impairment AUC values of bosentan in equilibrium above 9%, and the active metabolite.
in patients with moderate hepatic impairment exemastane associated with portal hypertension, the at steady state bosentan turned 4.7 times higher, and the active metabolite, Ro 48-5033 – 12.4 times higher than in  patients with preserved renal function.
The pharmacokinetics of bosentan in patients with severely impaired hepatic function  has not been studied. It is recommended to avoid the use  in patients with moderate to severe liver dysfunction .

Renal impairment
In patients with severe renal impairment  concentration in the bosentan plasma is reduced by about 10%. The concentration of bosentan metabolites in blood plasma increases by about 2-fold compared to patients with preserved renal function. In patients with impaired renal function does not require dose adjustment. The use of bosentan in patients undergoing hemodialysis has not been studied. Given the physical and chemical properties of bosentan and its high degree of binding to plasma proteins, a substantial clearance from the vascular bosentan during hemodialysis is expected.

Indications

Treatment of pulmonary arterial hypertension  to improve exercise capacity and clinical symptoms in patients II-IV functional class  classification, adults and children older than 3 years, including:

 

  • Primary (idiopathic and familial) exemastane
  • PAH secondary to scleroderma background in the absence of significant interstitial lung disease,
  • PAH associated with congenital heart disease, and, in particular, violations of hemodynamic parameters by type of Eisenmenger syndrome.

Reducing the number of new digital ulcers in adults with progressive systemic sclerosis and ulcerative lesions of the extremities.

Contraindications:

 

  • Hypersensitivity to bosentan or any of the components;
  • Violations of the liver secondary to severe function (7 or more points on a scale Child-Pugh);
  • The initial increase in activity of “liver” transaminases: aspartate aminotransferase  and / or alanine aminotransferase  levels to more than 3 times the upper limit of normal;
  • Concomitant use with cyclosporine;
  • Use of the drug in women of reproductive age who are not using reliable methods of contraception;
  • Age up to 3 years (the solid dosage form).

Carefully

Severe hypotension (systolic blood pressure less than 85 mmHg..), Chronic obstructive pulmonary disease (COPD), lung liver function abnormalities exemastane (insufficient clinical data on the efficacy and safety).

Do not set the effect  on the healing of existing digital ulcers.