Pharmacology: Pharmacodynamics: Imatinib 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. It inhibits proliferation and induces apoptosis in Bcr-Abl-positive cell lines, as well as fresh leukemic cells from Ph+ CML. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from patients with CML.
In vivo, it inhibits tumor growth of Bcr-Abl-transfected murine myeloid cells, as well as Bcr-Abl-positive leukemia lines derived from patients with CML in blast crisis.
Imatinib also is an inhibitor of the receptor tyrosine kinases for PDGF and stem-cell factor, c-kit, and inhibits PDGF- and stem-cell factor-mediated cellular events. In-vitro, imatinib inhibits proliferation and induces apoptosis in GI stromal tumor cells, which express an activating c-kit mutation.
Pharmacokinetics: Absorption/Distribution: Imatinib is well absorbed after oral administration, with maximal drug concentration (Cmax) achieved within 2 to 4 hours postdose. Mean absolute bioavailability is 98%. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 to 1000 mg. There is no significant change in the pharmacokinetics of imatinib upon repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when imatinib 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 alpha-1 acid glycoprotein.
Metabolism: CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other CYP enzymes, such as 1A2, 2D6, 2C9, and 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 approximately 15% of the AUC for imatinib. The plasma-protein binding of the N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that imatinib is a potent competitive inhibitor of CYP2C9, 2D6, and 3A4/5, with Ki values of 27, 7.5 and 8 mcM, respectively.
Excretion: Elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces); the remainder was metabolites.
Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative (CGP74588), were approximately 18 and 40 hours, respectively.