Функциональное состояние печени как один из факторов обеспечения безопасности и эффективности терапии эверолимусом

Abstract

Actuality. Everolimus is an oral drug from the group of immunodepressives, a derivative of macrocyclic lactone, the mechanism of action of which is to inhibit serine-threonine kinase (mTOR), which is the Central mechanism in the proliferation of T cells. The drug is used in a complex scheme of immunosuppressive therapy to prevent rejection of kidney and heart transplant. Everolimus is characterized by a narrow therapeutic interval and demonstrates clinically significant variability of pharmacokinetics due to the peculiarities of resorption, biotransformation, elimination, and inter-drug interactions. Liver pathology occupies an important place in the structure of factors influencing the achievement of target concentrations of everolimus. Such lability of the unfavorable pharmacokinetics of the influence of et on the achievement of target concentrations of the drug in the blood, reducing the effectiveness of the therapy or increase the risks of side effects. Thus, patients taking everolimus need regular laboratory control of the drug concentration. Special control require patients with concomitant pathology of the liver. The aim of the study was to consider the factors affecting the achievement of target concentrations of everolimus with a closer study of the contribution of liver disease to the effectiveness and safety of therapy, as well as the possibility of using laboratory methods for the optimization of therapy. Material and methods of research. To study the factors influencing the achievement of the target concentrations of everolimus in the blood, we studied the current literature data and the results of the study of everolimus pharmacokinetics in patients after heart transplantation on the background of liver disease. To evaluate the contribution of pathology of the liver in the efficacy and safety of therapy, as well as the possibility of using laboratory techniques to optimize the therapy were conducted the original prospective research in the group of patients (n=16) who underwent the transplantation of the heart in the i medical research named after V. A. Almazov Mr 2012-2016, as well as the host merely-Mus at a dose of 1.25 mg/day to about 5.4 mg/day (mean dose 2.5 mg/day). Patients were observed in the period from 2016-2017. Patients were the distribution of HN into two groups in accordance with the presence and absence of the signs of Neal-Cogolin fatty liver disease (NAFLD). To control the concentrations of everolimus in whole blood, a method of high-performance liquid-bone chromatography with mass-spetromtric detection was used, for the use of which an original analytical technique for the quantitative determination of everolimus in whole blood was developed in the laboratory of therapeutic drug monitoring of the national medical research of the Ministry of health of the Russian Federation. Results. According to the literature data, the achievement of the target concentrations of everolimus is influenced by the activity of the efflux vector of p-glycoprotein drugs, the rate of metabolic transformations of the drug mediated by cytochromes CYP3A4, 3A5, 2C8, inter-drug interactions, consumption of fatty foods, as well as non-compliance with the prescribed treatment regimen. Non-alcoholic fatty liver disease is one of the leading factors adversely affecting achievement of target everolimus concentrations which significantly increases the risk of toxic effects. For laboratory monitoring in the laboratory of therapeutic drug monitoring of the medical research center (Russia) was developed an original analytical technique for the quantitative determination of everolimus in human whole blood, successfully validated. Conclusion. Everolimus is a powerful immunosuppressant, which is actively and successfully used in patients as part of immunosuppressive therapy after transplantation of solid organs. However, it has a high risk of side effects or reduced efficiency, because it has a narrow therapeutic interval and pronounced variability of pharmacokinetics. One of the leading factors influencing the maintenance of target concentrations is nonalcoholic fatty liver disease. To reduce the risk of side effects and ensure the proper effectiveness of therapy with everolimus, monitoring of drug concentrations and assessment of liver function should be carried out.