Imatinib - How It Works
Clinical pharmacology details from the US FDA-approved label: how Imatinib works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo , imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-K
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML.
Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.
Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients.
In vivo , imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events.
In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.
12.3 Pharmacokinetics The pharmacokinetics of imatinib mesylate have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients.
The pharmacokinetics of imatinib mesylate are similar in CML and GIST patients.
Absorption and Distribution Imatinib is well absorbed after oral administration with C max achieved within 2 to 4 hours post-dose.
Mean absolute bioavailability is 98%.
Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg.
There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when imatinib mesylate is dosed once daily.
At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein.
Elimination Metabolism CYP3A4 is the major enzyme responsible for metabolism of imatinib.
Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism.
The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4.
It shows in vitro potency similar to the parent imatinib.
The plasma AUC for this metabolite is about 15% of the AUC for imatinib.
The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.
Excretion Imatinib elimination is predominately in the feces, mostly as metabolites.
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetics of imatinib mesylate have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. The pharmacokinetics of imatinib mesylate are similar in CML and GIST patients. Absorption and Distribution Imatinib is well absorbed after oral administration with C max achieved within 2 to 4 hours post-dose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when imatinib mesylate is dosed once daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein. Elimination Metabolism CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Excretion Imatinib elimination is predominately in the