Overview
Characterization of the substance
Pharmacology
Bozentan - non-selective antagonist of endothelin receptors type ETBUT and ETAT. Endothelin 1 (ETone) - a powerful vasoconstrictor, when bound to ET receptorsBUT and ETAT, located in the endothelium and vascular smooth muscle cells, induces fibrosis, cell proliferation, hypertrophy and myocardial remodeling, and exhibits pro-inflammatory activity. ET concentrationone in tissues and blood plasma increases with some cardiovascular diseases and pathology of connective tissue, including with pulmonary arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischemia, systemic arterial hypertension and atherosclerosis. Bozentan competitively blocks ET receptorsone and does not bind to other receptors, reduces the resistance of systemic and pulmonary vessels, which leads to an increase in cardiac output without increasing heart rate.
When taking bosentan orally in a dose of up to 500 mg, an increase in Cmax and AUC occurs in proportion to the dose, with the introduction of a higher dose - disproportionately and more slowly. The oral bioavailability of bosentan is 50%, food intake does not affect bioavailability. TCmax 3-5 hours. The volume of distribution after a single iv injection of a dose of 250 mg is 18 liters. Communication with proteins - 98%. Bozentan is metabolized in the liver with the participation of isoenzymes of cytochrome P450, CYP2C9 and CYP3A4, with the formation of 3 metabolites (one has pharmacological activity). T1/2 - 5.4 h. Ground clearance - 8.2 l / h. Bozentan is excreted mainly with bile, less than 3% - with urine. Average AUC in children is lower than in adults suffering from pulmonary arterial hypertension. With a CC of 15-30 ml / min, the concentration of bosentan in blood plasma decreases by 10%, while the concentration of metabolites increases by 2 times.
Application
Bozentan: Contraindications
Hypersensitivity, moderate to severe liver failure, initial increase in AST and / or ALT activity by more than 3 times, simultaneous use of cycloserine A, women of reproductive age (not using reliable methods of contraception during treatment), pregnancy, lactation, children's age (up to 3 years).
Pregnancy and lactation
Bozentan is contraindicated in pregnancy and lactation.
Bozentan: Side Effects
From the CCC side: peripheral edema, severe vasodilation (asymptomatic decrease in blood pressure, flushing of the face, Bosleer of the face, feeling hot), palpitations.
From the nervous system: headache, fatigue.
From the digestive system: dry mouth, dyspepsia, impaired liver function, gastroesophageal reflux, rectal bleeding.
Hematopoietic organs: anemia.
On the part of the respiratory system: nasopharyngitis, pneumonia, upper respiratory tract infection.
Allergic reactions: itchy skin.
Laboratory indicators: increased activity of “liver” enzymes (in the first 16 weeks of therapy, asymptomatic, returns to the initial within a few days to 9 weeks spontaneously or after a dose reduction or drug withdrawal), decreased Hb.
Interaction
Bozentan undergoes metabolism with the participation of cytochrome CYP and its isoenzymes CYP2C9 and CYP3A4. Inhibition of the CYP3A4 isoenzyme increases the concentration of bosentan in the blood plasma. The effect of inhibition of the CYP2C9 isoenzyme on the concentration of bosentan in blood plasma was not studied. For combined use, care should be taken. The simultaneous use with fluconazole, which mainly has an inhibitory effect on the CYP2C9 isoenzyme and only a slight effect on the CYP3A4 isoenzyme, may be accompanied by an increase in the concentration of bosentan in blood plasma. This combination is not recommended. For the same reason, the simultaneous use of the drug and powerful inhibitors of the CYP3A4 isoenzyme (e.g. ketoconazole, itraconazole or ritonavir) and a CYP2C9 isoenzyme inhibitor (e.g. voriconazole) is not recommended.
Bozentan is an inducer of isoenzymes CYP2C9 and CYP3A4. According to an in vitro study, the role of an inducer of the CYP2C19 isoenzyme is also assumed. Therefore, with the simultaneous use of bosentan and drugs, the metabolism of which is mediated by these isoenzymes, their plasma concentration decreases. It should be borne in mind the possibility of reducing the effectiveness of drugs whose metabolism is carried out with the participation of the same isoenzymes. You may need a dose adjustment of the simultaneously used drugs after starting the drug, changing its dose or canceling.
Glibenclamide - the risk of increased activity of "liver" Bosleer concomitant use with bosentan is not recommended.
Fluconazole significantly increases the concentration of bosentan in blood plasma; concomitant use with bosentan is not recommended.
The simultaneous use of bosentan and warfarin does not lead to clinically significant changes in the international normalized ratio (INR); dose adjustment of warfarin or similar oral anticoagulants at the beginning Bosleer bosentan therapy is not required, however, more intensive monitoring of INR at the beginning of use and at the stage of increasing the dose of bosentan is recommended.
The simultaneous use of 125 mg of bosentan 2 times a day for 5 days reduces the concentration of simvastatin and its active metabolite in blood plasma by 34% and 46%, respectively, the concentration of bosentan in blood plasma does not change (it is recommended to control cholesterol concentration with subsequent dose adjustment).
The simultaneous use of bosentan in a dose of 62.5 mg of the drug 2 times a day for Bosleer days and ketoconazole increases the concentration of bosentan in 2 times, however, dose adjustment of bosentan is not required. When using combination therapy in combination with a CYP2C9 inhibitor, in patients with impaired metabolism of CYP3A4, the risk of a significant increase in the concentration of bosentan in the blood plasma increases, which can lead to the development of potentially serious side effects.
The simultaneous use of digoxin and bosentan at a dose of 500 mg 2 times a day for 7 days reduces AUC, Cmax and Cmin digoxin by 12.9 and 23%, respectively, which is not clinically significant.
Bozentan: Dosage and Administration
Inside, in the morning and in the evening, regardless of food intake. The initial dose of bosentan is 62.5 mg 2 times a day for 4 weeks, then the dose is increased to a maintenance dose - 125 open 2 times a day.