An antitumor medicine, an immunomodulator. Lenalid is the representative of a new class of immunomodulators (IMiDsSM), which has both immunomodulatory and anti-angiogenic properties.
Lenalidomide inhibits the secretion of proinflammatory cytokines, including TNF-α, interleukin-1β (IL-1β), IL-6 and IL-12, from liposaccharide (LPS) -stimulated peripheral mononuclear blood cells (PMCK).
Lenalidomide increases the production of anti-inflammatory cytokine IL-10 from LPS-stimulated PMCK, resulting in inhibition of expression, but not of the enzymatic activity of COX-2.
Lenalidomide induces the proliferation of T cells and increases the synthesis of IL-2 and interferon-1γ, and also increases the cytotoxic activity of the own killer cells.
Lenalidomide inhibits the proliferation of cells of various lines of hematopoietic tumors, mainly those that have cytogenetic defects of the chromosome 5.
In the differentiation model of erythroid progenitor cells, lenalidomide induces fetal hemoglobin expression, judging by the differentiation of CD34 + stem hemopoietic cells.
Lenalidomide inhibits angiogenesis, blocking the formation of microvessels and endothelial canals, as well as the migration of endothelial cells in the in vitro angiogenesis model. In addition, lenalidomide inhibits the synthesis of proangiogenic vascular endothelial growth factor by means of PC-3 prostate cancer cells.
Clinical efficacy and safety of Lenalid were confirmed by the results of two multicenter random phase III trials in which patients with multiple myeloma received Lenalid together with dexamethasone or only one dexamethasone as 2nd line therapy. For all the efficacy criteria, including the percentage of complete and partial responses, combined therapy with Lenalid and dexamethasone was superior to dexamethasone monotherapy.
Lenalidomide, in healthy volunteers, was rapidly absorbed after oral administration. The maximum concentration in the blood plasma after 1.5 hours after taking the medicine. Eating does not affect the extent of absorption (AUC) but reduces the maximum plasma concentration (Cmax) by 36%. Cmax and AUC increased in proportion to the dose increase. Multiple administration in the recommended dose does not lead to accumulation of the medicine.
In patients with multiple myeloma, the maximum plasma concentrations are 4.0 hours after taking the medicine. AUC and Cmax increase in proportion to the dose after a single and multiple administration. The degree of absorption (AUC) in patients with multiple myeloma is 57% higher than in healthy male volunteers.
Under laboratory conditions, binding to plasma proteins is about 30%.
Metabolism and excretion: The
The metabolic profile of lenalidomide in the human body has not been studied. In healthy volunteers, approximately two-thirds of lenalidomide is excreted unchanged through the kidneys. The half-life is about 3 hours.
Pharmacokinetics in special clinical cases
C max does not differ in patients with normal and impaired renal function. In this case, the excretion of lenalidomide slows in proportion to the degree of renal function impairment. Reducing the CC below 50 ml/min is accompanied by an increase in AUC. T 1/2 lenalidomide rises from about 3.5 hours (in patients with QC above 50 mL/min) to about 9 hours (in patients with SC less than 50 mL/min).
The pharmacokinetics of lenalidomide in patients with impaired liver function has not been studied.
Lenalid is intended only for oral administration.
Capsules Lenalid cannot be broken or chewed. It is recommended to take the medicine every day at the same time before or after eating, squeezed with water.
The recommended initial dose of Lenalide is 25 mg 1 time/day in 1-21 days of repeated 28-day cycles.
Dexamethasone 40 mg is prescribed 1 time per day at 1-4, 9-12 and 17-20 days of each 28-day cycle during the first 4 cycles of therapy, and then at 40 mg 1 time/day in 1-4 days each subsequent 28-day cycle.
Modification of the dose should be made on the basis of clinical and laboratory data. The doctor should carefully select the dose of dexamethasone, taking into account the patient’s condition and the stage of the disease.
If less than 12 hours have passed after the missed Lenalid dose, the patient may take this missed dose of the medicine, and if more than 12 hours have elapsed, the missed dose should not be taken. The next dose of Lenalid should be taken the next day, at the usual time.
Lenalidomide treatment should not be started if the absolute number of neutrophils is <1.0 × 10 9 / L and/or the platelet count is <75 × 10 9 / L or, depending on the infiltration of bone marrow by plasma cells, the platelet count <30 × 10 9 / l.
A special plan of action for an overdose of lenalidomide in patients with multiple myeloma is not currently developed, despite the fact that in studies on determining the dose range, some patients received doses up to 150 mg, and in studies of single-dose exposure up to 400 mg of the medicine. Toxic manifestations, which limited the dose in these studies, were exclusively hematological.
In case of an overdose, symptomatic maintenance therapy is recommended.
Erythropoietic agents, as well as other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in patients with multiple myeloma who take lenalidomide in combination with dexamethasone.
Mutual influence on the metabolism of lenalidomide and other medicines is unlikely in connection with the fact that lenalidomide is not metabolized by the cytochrome P450 system.
Simultaneous administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin (C max digoxin was 114%, and AUC 0-∞ 108%). Thus, against the background of lenalidomide treatment, it is recommended to monitor the concentration of digoxin.
Dexamethasone, which is an obligatory component of the treatment regimen with Lenalide, can reduce the effectiveness of oral contraceptives. To effectively prevent pregnancy, use the medicines indicated in the Pregnancy Protection Program.
There was no mutual influence on the pharmacokinetic parameters of lenalidomide and warfarin. Taking into account the use of dexamethasone in combination with lenalidomide, one can not exclude the influence of the latter on the effects of warfarin. Thus, against a background of combined therapy with lenalidomide and dexamethasone, careful monitoring of the concentration of warfarin is recommended.
Pregnancy and lactatemia
The medicine is contraindicated in pregnancy and lactation (breastfeeding).
Women of reproductive age should be treated with effective methods of contraception during the treatment with Lenalid. The use of lenalidomide should be discontinued if a woman is diagnosed with pregnancy.
It is not known whether lenalidomide penetrates breast milk. In this regard, during the treatment with lenalidomide, breastfeeding should be discontinued.
In patients receiving Lenalid/dexamethasone, the following adverse reactions were most common : neutropenia (39.4%), muscle weakness (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramps (20.1%), thrombocytopenia (18.4% %), anemia (17%), diarrhea (14.2%), rash (10.2%).
The most severe adverse reactions: venous thromboembolism (deep vein thrombosis, pulmonary embolism, pulmonary embolism), grade 4 neutropenia.