fluoxymesterone

fluoxymesterone

In studies fluoxymesterone in vitro fluoxymesterone provides ingibiruyushee action on glucosylceramide synthase at IC50 concentrations in the 20-37 micromolar. Furthermore, in experiments in vitro it has also been found to influence its ipgibiruyuschee nelizosomalnuyu glyukoziltseramidazu.In fluoxymesterone as a result of hereditary metabolic disorders is no natural degradation of glucosylceramide, which leads to the accumulation of substances in the lysosomes and is accompanied by pathological changes in many organs. fluoxymesterone okazyvetsya glyukoziltseramidsintazu inhibitory effect on that enzyme is responsible for the first step of the synthesis of most glycolipids. Glyukoziltssramidsiitazy Inhibitory effect underlies substratsnizhayuschey treatment of Gaucher disease.

Niemann-Pick disease type C (sphingomyelin lipidosis) – a very rare disease that develops as a result of violation of intracellular transport of lipids and manifesting neurodegenerative changes. The disease is characterized by a consistently progressive course, high lethality. It is believed that neurological changes in disease Niemann-Pick type C develops secondary to the accumulation of glycosphingolipids in neuronal and glial cells.

Pharmacokinetics

Farmakokinetichsskie fluoxymesteronea parameters studied in healthy volunteers, a limited number of patients with Gaucher disease type 1, in patients with Fabry disease, HIV-infected patients, in adults and children with Niemann-Pick disease type C and Gaucher disease type 3. Suction

Farmakokinetichsskie fluoxymesteronea parameters are directly proportional to the dose and time dependent. In healthy volunteers when administered fluoxymesterone is rapidly absorbed. The maximum concentration (Cmax ) is determined in blood plasma after about 2 h. The absolute bioavailability of fluoxymesteronea not installed. When co-administered the drug with food its absorption rate decreases (C max is decreased by 36% and the time to reach C max (t max ) is increased by 2 hours), the degree of absorption of the drug when receiving it from the food was not significantly reduced (area under the curve “concentration -time »(AUC) is reduced by 14%).

Distribution

fluoxymesteronea volume of distribution is 83 liters. fluoxymesterone does not bind to plasma proteins.

Metabolism and excretion

fluoxymesterone is derived mainly (70-80% of the administered dose) through the kidneys in unchanged form. Clearance (CL / F) of fluoxymesteronea 230 ± 39 ml / min, poluvyvedepiya period averages 6-7 hours. In healthy volunteers after oral administration of 100 mg of 14 C-labeled it found that 83% of the radioactivity eliminated via the kidneys and 12% – in the intestine.

The main metabolite found in the urine, – fluoxymesteronea glucuronide, it is 5% of the dose fluoxymesteronea. Half-life of the radioactive material is 150 hours, it is assumed the presence of one or more metabolites with very long half-life. Metabolite, which would have a duration of action is not set, however, may occur, and its accumulation if the concentration exceeds the concentration fluoxymesteronea in equilibrium.

Farmakokinetichsskie indicators fluoxymesteronea in adult patients with type 1 Gaucher disease and Niemann-Pick disease type C do not differ from those in healthy volunteers.

Farmakokinetichsskie parameters studied in children with type 3 Gaucher disease in 3-15 years of age, children with Niemann-Pick disease type C aged 5-16 years. Application fluoxymesteronea in children at a dose of 200 mg, with a correction depending on body surface area, accompanied by an almost twofold increase in C max and AUC compared with the corresponding values of C max and AUC after administration of 100 mg fluoxymesteronea in Gaucher disease type 1 and also showed a linear dependence . At equilibrium concentration fluoxymesteronea 6 in the cerebrospinal fluid of patients with the disease type 3 Gosche was 31.4 – 67.2% contained in blood plasma.

Pharmacokinetics in special groups

Demographic parameters , demographic parameters such as the IOL, age, race, and body mass index did not have a clinically significant effect on the parameters farmakokinetichsskie fluoxymesteronea. Accordingly, the correction of the dose according to the above parameters required.

Elderly patients Farmakokinetichsskie fluoxymesteronea parameters in patients older than 70 years have not been studied.

Patients with hepatic insufficiency Due to the fact that fluoxymesterone is not metabolized by the liver, farmakokinetichsskie fluoxymesteronea parameters have not been studied in patients with hepatic insufficiency.

Patients with renal impairment Limited data, obtained in patients with Fabry disease and impaired renal function exhibit a decrease in clearance fluoxymesteronea as deterioration of renal function. In mild and medium-severe renal insufficiency fluoxymesteronea clearance decreased by 40% and 60%, respectively. Data in severe renal insufficiency limited to two patients (creatinine clearance was 18-29 ml / min), however, can not be extrapolated towards lower values. These data suggest a decrease in clearance of 70% or lower in patients with severe renal failure.

Indications

  • For oral treatment of adult patients with type 1 Gaucher disease and mild to moderate severity, which does not fit the enzyme replacement therapy.
  • For the treatment of progressive neurological symptoms in adults and children with Niemann-Pick disease type C.

Contraindications

  • Hypersensitivity to any component of the drug.
  • Severe renal insufficiency (creatinine clearance <30 mL / min / 1.73 m 2 ).
  • Children under 18 years of age in patients with Gaucher disease type 1 (no clinical experience).
  • Adult patients older than 70 years (no clinical experience).

Carefully

  • Hepatic and moderate renal insufficiency (creatinine clearance 30-50 ml / min / 1.73 m 2 ).
  • In children with Niemann-Pick disease type C up to 4 years (application experience is limited).

Application of pregnancy and during breastfeeding

fluoxymesteronea controlled studies in pregnant women have been conducted. Experimental studies suggest the presence of at fluoxymesteronea reproductive toxicity, including obstructed labor. The potential risk in humans is unknown. fluoxymesterone crosses the placental barrier, fluoxymesterone should not be used during pregnancy. Women of childbearing age should use reliable methods of contraception. Not known whether fluoxymesterone passes into breast milk arrives. Zaveska The drug should not be given during lactation.

Dosing and Administration

Zaveska The drug, taken orally, regardless of food intake. Treatment with Zaveska should carry a doctor, having sufficient experience in treatment of diseases of “accumulation”. In type 1 Gaucher disease in adults The recommended starting dose is 100 mg 3 times a day at regular intervals. Dose can be reduced to 100 mg 1-2 times a day in patients with diarrhea or tremor.

When disease Niemann-Pick type C in adults and children 12 years and older the recommended starting dose is 200 mg 3 times a day. Children under 12 years of age the dose is calculated on the basis of body surface area. winbol