July 31, 2015
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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 signalling 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 signalling at clinically relevant concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.


Absorption and Distribution

The mean oral bioavailability of gefitinib is 60%, with peak plasma levels occurring 3-7 hours after dosing. Food does not alter gefitinib bioavailability to a clinically meaningful extent. IRESSA 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 Pglycoprotein (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. Steady state plasma concentrations are achieved within 10 days after daily dosing. Excretion of gefitinib and its metabolites is predominantly via the feces (86%), with renal elimination accounting for less than 4% of the administered dose.

Specific Populations

Age, gender, body weight, ethnicity or renal function: Population pharmacokinetic analyses suggest that patient age, body weight, ethnicity (populations included) or creatinine clearance (above 20 mL/min) has no clinically meaningful effect on predicted steady state trough concentration of gefitinib. Population pharmacokinetic analyses of Study 1 showed that women had 27% higher exposure than men; however, this difference was not identified in the analyses of other gefitinib clinical studies. No dose adjustment based on patient gender is recommended.

Hepatic Impairment: The systemic exposure of gefitinib was compared between patients with mild, moderate, or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group). The mean systemic exposure (AUC0-∞) was increased by 40% in patients with mild impairment, 263% in patients with moderate impairment, and 166% in patients with severe hepatic impairment. In a study comparing 13 patients with liver metastases and moderate hepatic impairment to 14 patients with liver metastases and normal hepatic function, the systemic exposure of gefitinib was similar [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

CYP2D6 Poor metabolizer: CYP2D6 metabolizes gefitinib to O-desmethyl gefitinib in vitro. In healthy CYP2D6 poor metabolizers, O-desmethyl gefitinib concentration was not measurable and the mean exposure to gefitinib was 2-fold higher as compared to the extensive metabolizers. This increase in exposure in CYP2D6 poor metabolizers may be clinically important because some adverse drug reactions are related to higher exposure of gefitinib. No dose adjustment is recommended in patients with a known CYP2D6 poor metabolizer genotype, but these patients should be closely monitored for adverse reactions. The impact of CYP2D6 inhibiting drugs on gefitinib pharmacokinetics has not been evaluated. However, similar precautions should be used when administering CYP2D6 inhibitors with IRESSA because of the possibility of increased exposure in these patients.

An exploratory exposure response analysis showed an increase in the incidence of interstitial lung disease (ILD) with a greater than 2 fold increase in the gefitinib exposure [see WARNINGS AND PRECAUTIONS].

Drug-Drug Interactions

Strong CYP3A4 Inducer

Concomitant administration of rifampicin (600 mg QD for 16 days), a strong inducer of CYP3A4, with gefitinib (500 mg single dose on Day 10 of gefitinib administration) reduced mean AUC of gefitinib by 83% [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].

CYP3A4 Inhibitor

Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor of CYP3A4, with gefitinib (250 mg single dose on Day 4 of itraconazole administration) to healthy male subjects, increased mean gefitinib AUC by 80% [see DRUG INTERACTIONS].

Drugs Affecting Gastric pH

Co-administration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above pH 5.0) to healthy subjects decreased mean gefitinib AUC by 47% [see DRUG INTERACTIONS].

In human liver microsome studies, gefitinib had no inhibitory effect on CYP1A2, CYP2C9, and CYP3A4 activities at concentrations ranging from 2-5000 ng/mL. At the highest concentration studied (5000 ng/mL), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43%.

Exposure to metoprolol, a substrate of CYP2D6, was increased by 30% when it was given on Day 15 of gefitinib dosing (500 mg daily for 28 days) in patients with solid tumors.

Clinical Studies

Non-Small Cell Lung Cancer (NSCLC)

Study 1

The efficacy and safety of IRESSA for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or L858R substitution mutations was demonstrated in a multicenter, single-arm, open-label clinical study (Study 1). A total of 106 treatment-naive patients with metastatic EGFR mutation positive NSCLC received IRESSA at a dose of 250 mg once daily until disease progression or intolerable toxicity. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.1 as evaluated by both a Blinded Independent Central Review (BICR) and investigators. Duration of response (DOR) was an additional outcome measure. Eligible patients were required to have a deletion in EGFR exon 19 or L858R, L861Q, or G719X substitution mutation and no T790M or S768I mutation or exon 20 insertion in tumor specimens as prospectively determined by a clinical trial assay. Tumor samples from 87 patients were tested retrospectively using the therascreen® EGFR RGQ PCR Kit.

The study population characteristics were: median age 65 years, age 75 years or older (25%), age less than 65 years (49%), white (100%), female (71%), never smokers (64%), WHO PS 0 (45%), WHO PS 1 (48%), WHO PS 2 (7%), and adenocarcinoma histology (97%). Sixty patients had exon 19 deletions (65%), 29 patients had L858R substitution (31%), while two patients each had tumors harboring L861Q or G719X substitution mutation.

The median duration of treatment was 8.0 months. Efficacy results from Study 1 are summarized below.

Table 3 : Efficacy Results in Study 1

Efficacy Parameter BICR1 Assessment
Investigator Assessment
Objective Response Rate3 (95% CI) 50% (41, 59) 70% (61, 78)
Complete Response Rate 0.9% 1.9%
Partial Response Rate 49% 68%
Median Duration of Response (months) 6.0 8.3
(95% CI) (5.6, 11.1) (7.6, 11.3)
1BICR, Blinded Independent Central Review
2 17 patients without target lesion at baseline detected by BICR were deemed non responders
3Determined by RECIST v 1.1

The response rates were similar in patients whose tumors had EGFR exon 19 deletions and exon 21 L858R substitution mutations. Two partial responses were observed in both patients whose tumors had G719X substitution mutation with duration of response of at least 2.8 months and 5.6 months, respectively. One of two patients whose tumors had L861Q substitution mutation also achieved a partial response with duration of response of at least 2.8 months.

Study 2

The results of Study 1 were supported by an exploratory analysis of a subset of a randomized, multicenter, open-label trial (Study 2) conducted in patients with metastatic adenocarcinoma histology NSCLC receiving first-line treatment. Patients were randomized (1:1) to receive IRESSA 250 mg orally once daily or up to 6 cycles of carboplatin/paclitaxel. The efficacy outcomes included progression-free survival (PFS) and objective response rate (ORR) as assessed by BICR.

The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive by the same clinical trial assay as used in Study 1 and had radiographic scans available for a retrospective assessment by BICR. In this subset, there were 88 IRESSA-treated patients and 98 carboplatin/paclitaxel-treated patients.

Demographic and baseline characteristics of this subset were a median age of 59 years, age 75 years or older (7%), age less than 65 (70%), Asian (100%), female (83%), never smokers (96%), adenocarcinoma histology (100%), and PS 0-1 (94%).

The median duration of treatment for IRESSA-treated patients was 9.8 months. The hazard ratio for PFS favored the IRESSA-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS of 10.9 months for the IRESSA-treated patients and 7.4 months for the carboplatin/paclitaxel-treated patients as assessed by BICR. In addition, the objective response rate was 67% (95% CI: 56, 77) for IRESSA-treated patients and 41% (95% CI: 31, 51) for carboplatin/paclitaxel-treated patients based on BICR assessment. The median duration of response was 9.6 months for IRESSA-treated patients and 5.5 months for carboplatin/paclitaxel-treated patients.

Last reviewed on RxList: 7/15/2015
This monograph has been modified to include the generic and brand name in many instances.

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