CLINICAL PHARMACOLOGY
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 α1-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:
Gefitinib has been evaluated in a Phase I pharmacokinetic trial in pediatric patients.
In pediatric patients with refractory solid tumors the maximum tolerated dose (MTD) of gefitinib was determined to be 400 mg/m2 given orally once-daily. At this dose the median steady-state peak plasma concentration was 2.2 mg/ml and the median steady-state area under curve was 29.3 mg.h/ml. These values are comparable to those observed in adults at 700 mg/day. The most frequent toxicities observed were rash and altered ALT and AST.
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 (see PRECAUTIONS section).
Renal Impairment:
No clinical studies were conducted with IRESSA in patients with severely compromised renal function (see PRECAUTIONS section). Gefitinib and its metabolites are not significantly excreted via the kidney (<4%).
Drug-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 in combination with gefitinib (500 mg daily for 28 days) in patients with solid tumors.
The production of O-desmethyl gefitinib has been shown, in vitro, to be via CYP2D6. The role of CYP2D6 in the metabolic clearance of gefitinib has been evaluated in a clinical trial in healthy volunteers genotyped for CYP2D6 status. In poor metabolizers no measurable levels of O-desmethyl gefitinib were produced. The range of gefitinib exposures achieved in both the extensive and the poor metabolizer groups were wide and overlapping but the mean exposure to gefitinib was 2-fold higher in the poor metabolizer group. The higher average exposures that could be achieved by individuals with no active CYP2D6 may be clinically relevant since adverse experiences are related to dose and exposure.
Rifampicin, an inducer of CYP3A4, reduced mean AUC of gefitinib by 85% in healthy male volunteers (see PRECAUTIONS-Drug Interactions and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor of CYP3A4, with gefitinib (250 mg single dose) to healthy male volunteers, increased mean gefitinib AUC by 88% (see PRECAUTIONS-Drug Interactions section).
Co-administration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above pH 5.0) reduced mean gefitinib AUC by 44% (see PRECAUTIONS-Drug Interactions section).
International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see PRECAUTIONS-Drug Interactions and ADVERSE REACTIONS sections).
Clinical Studies
Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Tumor Response Study - A multicenter clinical trial in the United States evaluated the tumor response rate of IRESSA 250 and 500 mg/day in patients with advanced non-small cell lung cancer whose disease had progressed after at least two prior chemotherapy regimens including a platinum drug and docetaxel. IRESSA was taken once daily at approximately the same time each day.
Two hundred and sixteen patients received IRESSA, 102 (47%) and 114 (53%) receiving 250 mg and 500 mg daily doses, respectively. Study patient demographics and disease characteristics are summarized in Table 1. Forty-one percent of the patients had received two prior treatment regimens, 33% three prior treatment regimens, and 25% four or more prior treatment regimens. Effectiveness of IRESSA as third line therapy was determined in the 142 evaluable patients with documented disease progression on platinum and docetaxel therapies or who had had unacceptable toxicity on these agents.
Table 1: Demographic and Disease Characteristics |
IRESSA Dose
|
|
Characteristic
|
250 mg/day
N = 66 (%)
|
500 mg/day
N = 76 (%)
|
|
Age Group
| | |
|
18 − 64 years
|
43 (65)
|
43 (57)
|
|
64 − 74 years
|
19 (29)
|
30 (39)
|
|
75 years and above
|
4 (6)
|
3 (4)
|
|
Sex
| | |
|
Male
|
38 (58)
|
41 (54)
|
|
Female
|
28 (42)
|
35 (46)
|
|
Race
| | |
|
White
|
61 (92)
|
68 (89)
|
|
Black
|
1 (2)
|
2 (3)
|
|
Asian/Oriental
|
1 (2)
|
2 (3)
|
|
Hispanic
|
0 (0)
|
3 (4)
|
|
Other
|
3 (5)
|
1 (1)
|
|
Smoking History
| | |
|
Yes (Previous or current
Smoker)
|
45 (68)
|
62 (82)
|
|
No (Never Smoked)
|
21 (32)
|
14 (18)
|
|
Baseline WHO Performance Status
| | |
|
0
|
14 (21)
|
9 (12)
|
|
1
|
36 (55)
|
53 (70)
|
|
2
|
15 (23)
|
14 (18)
|
|
Not recorded
|
1 (2)
|
0 (0)
|
|
Tumor Histology
| | |
|
Squamous
|
9 (14)
|
11 (14)
|
|
Adenocarcinoma
|
47 (71)
|
50 (66)
|
|
Undifferentiated
|
6 (9)
|
4 (5)
|
|
Large Cell
|
1 (2)
|
2 (3)
|
|
Squamous & Adenocarcinoma
|
3 (5)
|
7 (9)
|
|
Not Recorded
|
0 (0)
|
2 (3)
|
|
Current Disease Status
| | |
|
Locally Advanced
|
11 (17)
|
5 (7)
|
|
Metastatic
|
55 (83)
|
71 (93)
|
Table 2 shows tumor response rates and response duration. The overall response rate for the 250 and 500 mg doses combined was 10.6% (95% CI: 6%, 16.8%). Response rates appeared to be highly variable in subgroups of the treated population: 5.1% (4/79) in males, 17.5% (11/63) in females, 4.6% (5/108) in previous or current smokers, 29.4% (10/34) in nonsmokers, 12.4% (12/97) with adenocarcinoma histology, and 6.7% (3/45) with other NSCLC histologies. Similar differences were seen in a multinational study in patients who had received 1 or 2 prior chemotherapy regimens, at least 1 of which was platinum-based. In responders, the median time from diagnosis to study randomization was 16.7 months (range 8 to 34 months).
Table 2: Efficacy Results |
Efficacy Population
|
|
250 mg (N=66)
|
500 mg (N=76)
|
Combined (N=142)
|
|
Objective Tumor Response Rate (%)
|
13.6
|
7.9
|
10.6
|
|
95% CI
|
6.4− 24.3
|
3.0 − 16.4
|
6.0 − 16.8
|
|
Median Duration of Objective Response (months)
|
8.9
|
4.5
|
7.0
|
|
Range (months)
|
4.6 − 18.6
|
4.4 − 7.6
|
4.4 − 18.6
|
Non-Small Cell Lung Cancer (NSCLC): Refractory Disease Survival Study - A double-blind, placebo-controlled parallel-group trial randomized 1692 patients with advanced NSCLC to receive either IRESSA 250 mg daily plus Best Supportive Care or placebo plus Best Supportive Care. Patients had received 1 or 2 prior chemotherapy regimens and had progressed while receiving or within 90 days of the last dose of chemotherapy or were intolerant to the most recent prior chemotherapy regimen. The two treatment arms were well-balanced for demographic and disease-related patient characteristics. The primary endpoint of the study was survival. IRESSA did not significantly prolong survival (stratified log rank HR 0.89, P=0.11, Median 5.6 vs 5.1 months for IRESSA and placebo, respectively).
Non-Small Cell Lung Cancer (NSCLC); Studies of First-line Treatment in Combination with Chemotherapy - Two large trials were conducted in chemotherapy-naïve patients with stage III and IV non-small cell lung cancer. Two thousand one hundred thirty patients were randomized to receive IRESSA 250 mg daily, IRESSA 500 mg daily, or placebo in combination with platinum-based chemotherapy regimens. The chemotherapies given in these first-line trials were gemcitabine and cis-platinum (N=1093) or carboplatin and paclitaxel (N=1037). The addition of IRESSA did not demonstrate any increase, or trend toward such an increase, in tumor response rates, time to progression, or overall survival.
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