Gefitinib

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Sparingly soluble (<pH4)

2.70e-02 g/L

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

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Targeted therapies

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P264, P264+P265, P270, P273, P280, P301+P317, P302+P352, P305+P354+P338, P317, P318, P319, P321, P330, P332+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 80 reports by companies from 15 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In large early clinical trials, elevations in serum aminotransferase levels occurred in 9% to 13% of patients treated with standard doses of gefitinib, and 2% to 4% of patients had to stop therapy because of elevations above 5 times the upper limit of normal. Serum enzyme elevations typically arise after 4 to 12 weeks of treatment with a hepatocellular pattern. Immunoallergic and autoimmune features have not been described, but rash is common in patients receiving gefitinib. Most cases of liver injury due to gefitinib in the literature have been minimally or not symptomatic, and the injury resolved within 1 to 2 months of stopping the drug. Restarting therapy was usually but not always followed by rapid recurrence of serum enzyme elevations, and corticosteroid therapy did not appear to prevent this recurrence. In some instances, lower doses were tolerated with minimal or no ALT elevations. Periodic monitoring of liver tests during therapy is recommended. Despite the frequency of serum aminotransferase elevations during gefitinib therapy, cases of clinically apparent liver injury with jaundice are rare. Cases of severe and fatal hepatotoxicity have been reported to the sponsor and monitoring of liver tests during therapy is recommended.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Gefitinib

vMost-DILI-concern

4

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

L01XE02

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.

Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that binds to the adenosine triphosphate (ATP)-binding site of the enzyme. EGFR is often shown to be overexpressed in certain human carcinoma cells, such as lung and breast cancer cells. Overexpression leads to enhanced activation of the anti-apoptotic Ras signal transduction cascades, subsequently resulting in increased survival of cancer cells and uncontrolled cell proliferation. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. By inhibiting EGFR tyrosine kinase, the downstream signaling cascades are also inhibited, resulting in inhibited malignant cell proliferation.

Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.

Gefitinib has known human metabolites that include 4-Defluoro-4-hydroxy Gefitinib and O-Desmethyl Gefitinib.

S65743JHBS

GEFITINIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Protein Kinase Inhibitors

Gefitinib is a Kinase Inhibitor. The mechanism of action of gefitinib is as a Protein Kinase Inhibitor.

GEFITINIB

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Protein kinase inhibitors that inhibit TYROSINE PROTEIN KINASES.

Absorbed slowly after oral administration with a mean bioavailability of 60%. Peak plasma levels occurs 3-7 hours post-administration. Food does not affect the bioavailability of gefitinib.

Elimination is by metabolism (primarily CYP3A4) and excretion in feces. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.

1400 L [IV administration]

595 mL/min [IV administration]