Imatinib

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Very soluble in water at pH < 5.5 (mesylate salt)

1.46e-02 g/L

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

Targeted therapies

Danger

H315 (18.2%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P260, P263, P264, P264+P265, P270, P280, P302+P352, P305+P351+P338, P318, P321, P332+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 11 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Imatinib therapy is associated with three forms of acute liver injury: transient and usually asymptomatic elevations in serum enzymes during treatment, clinically apparent acute hepatitis, and reactivation of an underlying chronic hepatitis B.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

imatinib

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

L01XE01

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

L01EA01

Imatinib is a 2-phenylaminopyrimidine derivative neoplastic agent that belongs to the class of tyrosine kinase inhibitors. Although imatinib inhibits a number of tyrosine kinases, it is quite selective toward the BCR-ABL fusion protein that is present in various cancers. BCR-ABL pathway controls many downstream pathways that are heavily implicated in neoplastic growth such as the Ras/MapK pathway (cellular proliferation), Src/Pax/Fak/Rac pathway (cellular motility), and PI/PI3K/AKT/BCL-2 pathway (apoptosis pathway). Therefore, the BCR-ABL pathway is an attractive target for cancer treatment. Although normal cells also depend on these pathways for growth, these cells tend to have redundant tyrosine kinases to continually function in spite of ABL inhibition from imatinib. Cancer cells, on the other hand, can have a dependence on BCR-ABL, thus more heavily impacted by imatinib.

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutively active tyrosine kinase created by the Philadelphia chromosome abnormality in CML.Although the function of normal BCR is still unclear, ABL activation is overexpressed in various tumors and is heavily implicated in cancer cells growth and survival. Imatinib inhibits the BCR-ABL protein by binding to the ATP pocket in the active site, thus preventing downstream phosphorylation of target protein. 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.

CYP3A4 is the major enzyme responsible for the 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.

Imatinib has known human metabolites that include N-desmethylimatinib.

BKJ8M8G5HI

IMATINIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Bcr-Abl Tyrosine Kinase Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 2D6 Inhibitors

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Protein kinase inhibitors that inhibit TYROSINE PROTEIN KINASES.

Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 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 a steady state when Gleevec is dosed once daily.

Imatinib 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 being metabolites.

Population pharmacokinetics in adult CML patients estimated the steady-state volume of distribution of imatinib to be 295.0 ± 62.5 L.At a dose of 340 mg/m², the volume of distribution of imatinib in pediatric patients was calculated to be 167 ± 84 L.

Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicities.