everolimus
Fuentes regulatorias consultadas
Indicaciones aprobadas
- Cáncer de mama HR+/HER2− avanzado con exemestano; tumores neuroendocrinos pancreáticos, gastrointestinales o pulmonares; carcinoma renal avanzado; angiomiolipoma renal, astrocitoma subependimario de células gigantes y crisis de inicio parcial asociados a esclerosis tuberosa, según los criterios de cada indicación.
Contraindicaciones
Absolutas
- Hipersensibilidad clínicamente significativa a everolimus, otros derivados de rapamicina o excipientes.
Advertencias clínicas
- Vigila neumonitis no infecciosa, infecciones oportunistas, hipersensibilidad/angioedema, insuficiencia renal, mielosupresión y alteraciones metabólicas. Interrumpe o suspende según gravedad. — OpenFDA, set_id 01f7b5fb-be0d-4adf-acd2-6899018de966
- Inicia enjuague de dexametasona sin alcohol para prevenir estomatitis. Retén al menos 1 semana antes de cirugía electiva y no reinicies hasta al menos 2 semanas tras cirugía mayor y cicatrización adecuada. Evita vacunas vivas. — OpenFDA, set_id 01f7b5fb-be0d-4adf-acd2-6899018de966
Interacciones medicamentosas
- SeveraModuladores de CYP3A4 y P-gp
Mecanismo: Los inhibidores aumentan y los inductores reducen la exposición a everolimus.
Recomendación: Evita inhibidores potentes; reduce con inhibidores moderados y aumenta de forma controlada con inductores potentes, con TDM cuando corresponda.
OpenFDA, set_id 01f7b5fb-be0d-4adf-acd2-6899018de966
- SeveraIECA
Mecanismo: Puede aumentar el riesgo de angioedema.
Recomendación: Vigila estrechamente y suspende definitivamente everolimus si aparece angioedema clínicamente significativo.
OpenFDA, set_id 01f7b5fb-be0d-4adf-acd2-6899018de966
Eventos adversos
Comunes (≥1%)
estomatitis · infecciones · exantema · fatiga · diarrea · edema · náuseas · pérdida de apetito
Embarazo y lactancia
Puede causar daño fetal. Mujeres y hombres con parejas con capacidad de gestar deben usar anticoncepción durante el tratamiento y 8 semanas después. No amamantes durante el tratamiento y 2 semanas después.
Bibliografía reciente (PubMed)
Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuat
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. The presence of IgM monoclonal protein associated with ≥ 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis. Age, albumin, hemoglobin level, platelet count, β2 microglobulin, Lactate dehydrogenase (LDH), and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to combination regimens. Recommended first-line therapy can be chemoimmunotherapy or a covalent Bruton tyrosine kinase inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib. Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, pirtobrutinib, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection. Most patients succumb to causes unrelated to macroglobulinemia.
- Transplantation and immunosuppression: a review of novel transplant-related immunosuppressant drugs.
Immunosuppressive drugs used in the transplantation period are generally defined as induction and maintenance therapy. The use of immunosuppressants, which are particularly useful and have fewer side effects, decreased both mortality and morbidity. Many drugs such as steroids, calcineurin inhibitors (cyclosporine-A, tacrolimus), antimetabolites (mycophenolate mofetil, azathioprine), and mTOR inhibitors (sirolimus, everolimus) are used as immunosuppressive agents. Although immunosuppressant drugs cause many side effects such as hypertension, infection, and hyperlipidemia, they are the agents that should be used to prevent organ rejection. This shows the importance of individualized drug use. The optimal immunosuppressive therapy post-transplant is not established. Therefore, discovering less toxic but more potent new agents is of great importance, and new experimental and clinical studies are needed in this regard.Our review discussed the mechanism of immunosuppressants, new agents' discovery, and current therapeutic protocols in the transplantation.
The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer's disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In c
The growing availability of targeted therapies for patients with advanced oestrogen receptor-positive breast cancer has improved survival, but there remains much to learn about the optimal management of these patients. The PI3K-AKT and mTOR pathways are among the most commonly activated pathways in breast cancer, whose crucial role in the pathogenesis of this tumour type has spurred major efforts to target this pathway at specific kinase hubs. Approvals for oestrogen receptor-positive advanced breast cancer include the PI3K inhibitor alpelisib for PIK3CA-mutated tumours, the AKT inhibitor capivasertib for tumours with alterations in PIK3CA, AKT1, or PTEN, and the mTOR inhibitor everolimus, which is used irrespective of mutation status. The availability of different inhibitors leaves physicians with a potentially challenging decision over which of these therapies should be used for individual patients and when. In this Review, we present a comprehensive summary of our current understanding of the pathways and the three inhibitors and discuss strategies for the optimal sequencing of therapies in the clinic, particularly after progression on a CDK4/6 inhibitor.