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Pharmacological effect - antitumor.


Mechanism of action. Ibrutinib Therapeutic indications

 is a powerful low-molecular weight inhibitor of Bruton's tyrosine kinase (TCB). Ibrutinib forms a covalent bond with the cysteine residue (Cys 481) in the active centre of the TKB, resulting in persistent inhibition of enzymatic activity. TKB, a member of the Tes family of kinases, acts as an important signal molecule in metabolic pathways associated with the signal activity of antigenic B-cell receptors (BCR) and cytokine receptors. The BCR signaling pathway is involved in the pathogenesis of a number of B cell malignancies, including mantle cell lymphoma, diffuse coarse cell B cell lymphoma, follicular lymphoma, and B cell chronic lymphocytic leukemia. The key role of TKB in the signaling activity of B-cell surface receptors leads to activation of signaling pathways necessary for B-cell migration, their chemotaxis and adhesion. According to preclinical studies, ibrutinib inhibits the proliferation and survival of malignant B cells in vivo, as well as cell migration and their adhesion to substrates in vitro.

In patients with recurrent B-cell lymphoma >90% of active TBK center employment in peripheral blood mononuclear cells is observed for the period up to 24 hours after intake of ibrutinib in doses of ≥2.5 mg/kg/day (≥175 mg/day at an average weight of 70 kg).

Lymphocytosis. At the beginning of therapy, most patients (75%) with chronic lymphocytic leukaemia who received ibrutinib had a reversible increase in the number of lymphocytes (i.e. 50% or more of the baseline with absolute values above 5000/µL), often accompanied by a decrease in lymphadenopathy. This effect was also present in some patients (35%) with recurrent or refractory lymphoma from mantle cells receiving ibrutinib. The lymphocytosis observed is a reflection of the pharmacodynamic effect, and should not be considered a progression of the disease in the absence of other clinical manifestations. In both diseases, lymphocytosis usually developed during the first few weeks of treatment with ibrutinib (median 1.1 weeks) and was usually resolved at median 8 and 18.7 weeks in patients with recurrent or refractory mantle cell lymphoma and chronic lymphocytic leukemia, respectively.

A significant increase in the number of circulating lymphocytes (i.e. over 400000/µL) was observed in some patients.

Lymphocytosis. In a study of patients with mantle cell lymphoma, a temporary increase in lymphocyte levels (i.e. ≥50% increase compared to baseline and absolute values above 5000/µL) after inducing ibrutinib was observed in 33% of patients. Lymphocytosis developed during the first few weeks of ibrutinib therapy and was resolved with a median of 8 weeks.

In a study of patients with chronic lymphocytic leukemia, an increase in lymphocyte levels (i.e., ≥50% increase over baseline and absolute values above 5000/µL) was observed in 77% of patients after ibrutinib. Lymphocytosis developed during the first month of ibrutiniba therapy and was resolved with a median of 23 weeks.

Pharmacokinetics .

Suction. Ibrutinib is quickly absorbed after oral intake with a median Tmach 1-2 hours. Patients with various B-cell malignancies have no significant differences in the pharmacokinetics of ibrutinib. The concentration of ibrutinib in plasma is proportionally increased with increasing dose up to 840 mg. The equilibrium AUC value in patients at 560 mg dose is (953±705) ng/h/ml (mean ± standard deviation). A meal with food leads to an increase in ibrutinib concentration by about 2 times compared to an on an empty stomach meal (without meals from the previous evening).


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