Qualitinib Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: The mechanism of the clinical antitumor action of Gefitinib is not fully characterized. 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. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to Gefitinib.
Pharmacokinetics: Gefitinib is absorbed slowly after oral administration with mean bioavailability of 60%. Elimination is by metabolism (primarily CYP3A4) and excretion in feces. The elimination half-life is about 48 hours. Daily oral administration of Gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration. Steady state plasma concentrations are achieved within 10 days.
Absorption and Distribution: Gefitinib is slowly absorbed, with peak plasma levels occurring 3-7 hours after dosing and mean oral bioavailability of 60%. Bioavailability is not significantly altered by food. Gefitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1400 L following intravenous administration. In vitro binding of Gefitinib to human plasma proteins (serum albumin and 1-acid glycoprotein) is 90% and is independent of drug concentrations.
Metabolism and Elimination: Gefitinib undergoes extensive hepatic metabolism in humans, predominantly by 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.
Five metabolites were identified in human plasma. Only O-desmethyl Gefitinib has exposure comparable to Gefitinib. Although this metabolite has similar EGFR-TK activity to Gefitinib in the isolated enzyme assay, it had only 1/14 of the potency of Gefitinib in one of the cell-based assays.
Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life values of 595 ml/min and 48 hours, respectively, after intravenous administration. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.
Special Populations: In population based data analyses, no relationships were identified between predicted steady state trough concentration and patient age, body weight, gender, ethnicity or creatinine clearance.
Pediatric: There are no pharmacokinetic data in pediatric patients.
Hepatic Impairment: The influence of hepatic metastases with elevation of serum aspartate aminotransferase (AST/SGOT), alkaline phosphatase, and bilirubin has been evaluated in patients with normal (14 patients), moderately elevated (13 patients) and severely elevated (4 patients) levels of one or more of these biochemical parameters. Patients with moderately and severely elevated biochemical liver abnormalities had Gefitinib pharmacokinetics similar to individuals without liver abnormalities.
Renal Impairment: No clinical studies were conducted with Gefitinib in patients with severely compromised renal function. Gefitinib and its metabolites are not significantly excreted via the kidney (<4%).