Dasnib Mechanism of Action

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors. ATC code: L01XE06.
Pharmacology: Pharmacodynamics: Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases along with a number of other selected oncogenic kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ receptor. Dasatinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase with potency at concentration of 0.6-0.8 nM. It binds to both the inactive and active conformations of the BCR-ABL enzyme.
Mechanism of action: In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive and resistant disease. These non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression. Additionally, dasatinib inhibits SRC family kinases at subnanomolar concentrations. In vivo, in separate experiments using murine models of CML, dasatinib prevented the progression of chronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines grown at various sites, including the central nervous system.
Pharmacokinetics: The bioequivalence of a single dose of the Test Product (Dasatinib 140 mg film-coated tablets, containing 140 mg dasatinib per film-coated tablet) and the Reference Product (Sprycel 140 mg film-coated tablets, containing 140 mg dasatinib per film-coated tablet) was assessed under fasting conditions.
The pharmacokinetics parameters of 125 subjects were calculated and results were statistically analyzed to demonstrate bioequivalence in a randomized, two treatment, four period, two sequence, single dose, crossover design study. After oral administration of single dose of test product in the fasted state, the mean of the maximum plasma concentration (C_max) (Rate of absorption) was 190.794 ng/ml, the median T_max was 1.00 h. The extent of absorption is expressed in Area Under Curve AUC_0-t and AUC_0-~, the mean values were 592.62 ng·h/ml and 609.45 ng·h/ml respectively. The mean elimination half life (T_1/2) of Dasatinib 140 mg was 5.23 h. The ratios and confidence intervals between test and reference product were as following: for C_max the ratio was 105.18% (98.14%-112.73%), for AUC_0-t the ratio was 106.95% (101.84%-112.32%). The result of the study showed that the ratios and confidence intervals are within the acceptance range for bioequivalence, therefore it can be concluded that the test product, Dasatinib 140 mg film-coated tablets, is bioequivalence with the reference product.