The active ingredient is an inhibitor of a proliferative signal. Everolimus exerts an immunosuppressive effect by inhibiting the proliferation cells and consequently clonal expansion caused by specific interleukins such parabolan cycle.Everolimus inhibits intracellular signaling pathways that normally lead to cellular proliferation, triggered by the binding of these growth factors, with appropriate receptors. Everolimus blockade of this signal leads to a cessation of cell division at the stage of the cell cycle .
At the molecular level, everolimus forms a complex with the cytoplasmic protein . In the presence of everolimus is inhibited phosphorylation kinase stimulated by growth factor. Since phosphorylation kinase is under the control of , these data suggest that the complex-everolimus . Key regulatory protein that controls the cellular metabolism, growth and proliferation; violation function thus explains the cell cycle arrest caused by everolimus. Everolimus is thus different from the mechanism of action of cyclosporin. In preclinical models it was shown allotransplantation higher efficiency everolimus combination with cyclosporin, than when used in isolation of each.
everolimus effect is not limited effect on T cells. It inhibits the growth factor-stimulated proliferation of both hematopoietic and non-hematopoietic cells (such as smooth muscle cells). Growth factor-stimulated vascular smooth muscle cell proliferation, which is triggered in case of damage of endothelial cells results in the formation of neointima, it plays a key role in the pathogenesis of chronic rejection.
In experimental studies have shown inhibition of neointima formation in rats with aortic allograft.
After oral administration, maximum concentration parabolan cycle is achieved after 1 -2 hours. Patients after transplantation everolimus blood concentration proportional to the dose in the dose range from 0.25 mg to 15 mg. Based on the relative bioavailability parameter of dispersible tablets in comparison with conventional.
Influence of food: Cmax and AUC of everolimus are reduced by 60% and 16%, respectively, when taking a tablet dosage form with a very fatty foods. To minimize variability or Sertikan be taken only with food or only without it.
The distribution of
the concentration ratio of everolimus in blood and plasma concentration in the range of 17% to 73% and depends on the concentration values in the range. In healthy volunteers and patients with moderate hepatic impairment binding to plasma proteins is approximately 74%. The volume of distribution at the terminal in patients after renal transplantation are on maintenance therapy.
Everolimus is a substrate. The main metabolic pathways identified in man were monogidroksilirovanie. Two main metabolites formed by hydrolysis of a cyclic lactone. None of them has significant immunosuppressive activity. In the systemic circulation is primarily everolimus.
After administration of a single dose of radiolabeled everolimus to patients after a transplant receiving cyclosporine, the majority (80%) of radioactivity was determined in the stool, a small amount (5%) excreted in the urine. Unmodified or substance is determined in the urine or in the feces.
Pharmacokinetics at steady state
pharmacokinetics in patients with renal and heart transplant parabolan cycle receiving everolimus 2 times daily concurrently with cyclosporine in microemulsion form, were comparable. The equilibrium state is achieved at day 4 with a cumulation in blood at concentrations that are 2-3 times higher than the concentration in the blood after administration of the first dose. Upon receiving the Tmax is 1-2 hours of the drug. At doses of 0.75 mg and 1.5 mg 2 times daily averages comprise Exposure everolimus remains stable at all times during the first year after transplantation. With highly correlated with the AUC with a correlation coefficient, fluctuating between 0.86 and 0.94.
Pharmacokinetics in specific patient groups
Liver function abnormalities
in 8 patients with moderate to severe hepatic impairment of everolimus was increased approximately 2-fold compared with 8 healthy volunteers. Indicator was positively correlated with the concentration of serum bilirubin and prothrombin time and increasing negatively correlated with the concentration of serum albumin. If the concentration of bilirubin was> 34 mol / L, prothrombin time (prolongation of> 4 seconds) and / or albumin concentration was <35 g / l, then there was a trend to an increase in AUC levels in patients with moderate hepatic insufficiency .The impact of severe hepatic insufficiency (class C Child-Pugh) on the is not known, but probably it is the same, or more pronounced than the impact of moderate hepatic insufficiency.
post-transplant renal impairment (creatinine clearance 11 -107 ml / min) did not affect the pharmacokinetic parameters of everolimus.
In adult patients aged 16 to 70 years have seen a decrease in clearance of everolimus by 0.33% per year. Dose adjustment is not required.
Based on a population pharmacokinetic analysis of total clearance was parabolan cycle higher in blacks patients by an average of 20%.
Effect of exposure to efficiency
have kidney and heart transplant recipients within 6 months after transplantation was found between basal concentration of everolimus and frequency of biopsy-confirmed acute rejection and of thrombocytopenia.
- Prophylaxis of transplant rejection in adult kidney and heart transplant recipients with low and middle immunological risk receiving a basic immunosuppressive therapy with cyclosporine in the form of a microemulsion and corticosteroids.
- Hypersensitivity to everolimus, sirolimus, or other ingredients.