Gefitinib - How It Works
Clinical pharmacology details from the US FDA-approved label: how Gefitinib 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 The epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells and plays a role in the processes of cell growth and proliferation. Some EGFR activating mutations (exon 19 deletion or exon 21 point mutation L858R) within NSCLC cells have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis. Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking EGFR-dependent proliferation. Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells and plays a role in the processes of cell growth and proliferation.
Some EGFR activating mutations (exon 19 deletion or exon 21 point mutation L858R) within NSCLC cells have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis.
Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking EGFR-dependent proliferation.
Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR.
Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.
12.3 Pharmacokinetics Absorption and Distribution The mean oral bioavailability of gefitinib is 60%, with peak plasma levels occurring 3 to 7 hours after dosing.
Food does not alter gefitinib bioavailability to a clinically meaningful extent.
Gefitinib tablets can be administered with or without 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 α1-acid glycoprotein) is 90%, independent of drug concentrations.
Gefitinib is a substrate for the membrane transport P-glycoprotein (P-gp), but it is unlikely to influence gefitinib absorption as P-gp is saturated at higher 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 methoxysubstituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.
Five metabolites have been fully identified in fecal extracts and the major active component was O-desmethyl gefitinib produced by CYP2D6 metabolism and accounted for 14% of the dose.
Eight 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 of 48 hours after intravenous administration.
The inter-subject variability (coefficient of variation) for AUC in healthy subjects was 67%.
Daily oral administration of gefitinib to cancer patients resulted in a two-fold accumulation compared to single dose administration.
Pharmacokinetics
12.3 Pharmacokinetics Absorption and Distribution The mean oral bioavailability of gefitinib is 60%, with peak plasma levels occurring 3 to 7 hours after dosing. Food does not alter gefitinib bioavailability to a clinically meaningful extent. Gefitinib tablets can be administered with or without 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 α1-acid glycoprotein) is 90%, independent of drug concentrations. Gefitinib is a substrate for the membrane transport P-glycoprotein (P-gp), but it is unlikely to influence gefitinib absorption as P-gp is saturated at higher 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 methoxysubstituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolites have been fully identified in fecal extracts and the major active component was O-desmethyl gefitinib produced by CYP2D6 metabolism and accounted for 14% of the dose. Eight 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