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Pharmacotherapeutic group: Protein-tyrosine kinase inhibitor.
Pharmacology: Mechanism of action: Mechanism of action Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.
Pharmacodynamics: Imatinib is a protein-tyrosine kinase inhibitor, which potently inhibits the breakpoint cluster region-Abelson (Bcr-Abl) tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGFR, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. Constitutive activation of the PDGFR receptor or the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of myelodysplastic/myeloproliferative (MDS/MPD), hypereosinophilic syndrome/chronic eosinophilic leukaemia (HES/CEL) and dermatofibrosarcoma protuberans (DFSP). In addition, constitutive activation of c-Kit or the PDGFR has been implicated in the pathogenesis of systemic mastocytosis (SM). Imatinib inhibits signalling and proliferation of cell driven by dysregulated PDGFR and Abl kinase activity.
Organ function impairment: Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The free drug clearance of Imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represent only a minor elimination pathway for Imatinib (see DOSAGE & ADMINISTRATION, PRECAUTIONS).
Pharmacokinetics: This study was an open label, balanced, randomized, two treatment, two period, two sequence, crossover, single oral dose, bioequivalence study in healthy, adult, human male subjects under fed conditions. The study was conducted following an oral administration of one tablet 400 mg of the Test Product or one tablet 400 mg of the Reference Product.
Based on the pharmacokinetic parameters of Imatinib (N = 35), mean ± SD for Test Product and Reference Product showed: Tmax values were 3.000 (1.500 - 6.017) and 3.667 (2.000 - 8.000) hours, respectively; Cmax values were 1863.516 ± 597.8907 and 1877.598 ± 624.9066 ng/mL, respectively; AUC0-t values were 35209.652 ± 11864.6972 and 34795.946 ± 12311.5359 ng.h/mL, respectively; AUC0-∞ values were 36877.054 ± 12685.6667 and 36499.566 ± 13134.5348 ng.h/mL, respectively; λz values were 0.046 ± 0.0088 and 0.047 ± 0.0083 l/h, respectively; t1/2 values were 15.639 (3.0747) and 15.091 ± 3.0018 hours, respectively; AUC_%Extrap_obs values were 4.358 ± 3.5698 and 4.466 ± 3.3739 %, respectively.
Results from bioequivalence study for Test Product and Reference Product were as following: 90.00% Confidence Intervals of geometric means ratio of the two bioavailability parameters of Imatinib were 93.67 - 105.41% for Cmax, 97.15 - 107.33% for AUC0-t, and 97.09 - 107.14% for AUC0-∞.
Conclusion: These results showed that 400 mg Imatinib film coated tablet was bioequivalent to the reference product.
