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Alimta (Pemetrexed Disodium) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ALIMTA® , pemetrexed for injection, is an antifolate antineoplastic agent that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N -[4-[2-(2-amino-4,7-dihydro-4-oxo-1 H -pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6·7H2O and a molecular weight of 597.49. The structural formula is as follows:

ALIMTA is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 500-mg vial of ALIMTA contains pemetrexed disodium equivalent to 500 mg pemetrexed and 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

CLINICAL PHARMACOLOGY

PHARMACODYNAMICS

Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.

Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, is inversely proportional to the systemic exposure of ALIMTA. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 µg·hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.

PHARMACOKINETICS

The pharmacokinetics of pemetrexed administered as a single agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). The clearance decreases, and exposure (AUC) increases, as renal function decreases. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles. Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.

DRUG INTERACTIONS

Chemotherapeutic Agents --Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Vitamins --Coadministration of oral folic acid or intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes --Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. No studies were conducted to determine the cytochrome P450 isozyme induction potential of pemetrexed, because ALIMTA used as recommended (once every 21 days) would not be expected to cause any significant enzyme induction.

Aspirin --Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.

Ibuprofen --Daily ibuprofen doses of 400 mg qid reduce pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown (see Drug Interactions under PRECAUTIONS).

SPECIAL POPULATIONS

The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies.

Geriatric --No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.

Pediatric --Pediatric patients were not included in clinical trials.

Gender --The pharmacokinetics of pemetrexed were not different in male and female patients.

Race --The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.

Hepatic Insufficiency --There was no effect of elevated AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted (see PRECAUTIONS).

Renal Insufficiency --Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed in the presence of cisplatin decreases as renal function decreases, with increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min (see WARNINGS and DOSAGE AND ADMINISTRATION).

CLINICAL STUDIES

Malignant Pleural Mesothelioma --The safety and efficacy of ALIMTA have been evaluated in chemonaive patients with malignant pleural mesothelioma (MPM) in combination with cisplatin.

Randomized Trial: A multi-center, randomized, single-blind study in 448 chemonaive patients with MPM compared survival in patients treated with ALIMTA in combination with cisplatin to survival in patients receiving cisplatin alone. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of ALIMTA. Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B12 supplementation.

The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended (see DOSAGE AND ADMINISTRATION). Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 1.

Table 1: Summary of Patient Characteristics in MPM study
Patient characteristic Randomized and Treated Patients Fully Supplemented Patients
ALIMTA/cis
(N=226)
Cisplatin
(N=222)
ALIMTA/cis
(N=168)
Cisplatin
(N=163)
Age (yrs)
Median (range) 61 (29-85) 60 (19-84) 60 (29-85) 60 (19-82)
Gender (%)
Male 184 (81.4) 181 (81.5) 136 (81.0) 134 (82.2)
Female 42 (18.6) 41 (18.5) 32 (19.0) 29 (17.8)
Origin (%)
Caucasian 204 (90.3) 206 (92.8) 150 (89.3) 153 (93.9)
Hispanic 11 (4.9) 12 (5.4) 10 (6.0) 7 (4.3)
Asian 10 (4.4) 4 (1.9) 7 (4.2) 3 (1.8)
African descent 1 (0.4) 0 1 (0.6) 0
Stage at Entry (%)
I 16 (7.1) 14 (6.3) 15 (8.9) 12 (7.4)
II 35 (15.6) 33 (15.0) 27 (16.2) 27 (16.8)
III 73 (32.4) 68 (30.6) 51 (30.5) 49 (30.4)
IV 101 (44.9) 105 (47.2) 74 (44.3) 73 (45.3)
Unspecified 1 (0.4) 2 (0.9) 1 (0.6) 2 (1.2)
Diagnosis/Histology a (%)
Epithelial 154 (68.1) 152 (68.5) 117 (69.6) 113 (69.3)
Mixed 37 (16.4) 36 (16.2) 25 (14.9) 25 (15.3)
Sarcomatoid 18 (8.0) 25 (11.3) 14 (8.3) 17 (10.4)
Other 17 (7.5) 9 (4.1) 12 (7.1) 8 (4.9)
Baseline KPS b (%)
70-80 109 (48.2) 97 (43.7) 83 (49.4) 69 (42.3)
90-100 117 (51.8) 125 (56.3) 85 (50.6) 94 (57.7)
a Only 67% of the patients had the histologic diagnosis of malignant mesothelioma confirmed by independent review.
b Karnofsky Performance Scale.

Table 2 summarizes the survival results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.

Table 2: Efficacy of ALIMTA plus Cisplatin vs. Cisplatin in Malignant Pleural Mesothelioma
Randomized and Treated Patients Fully Supplemented Patients
Efficacy Parameter ALIMTA/cis
(N=226)
Cisplatin
(N=222)
ALIMTA/cis
(N=168)
Cisplatin
(N=163)
Median overall survival
(95% CI)
12.1 mos
(10.0-14.4)
9.3 mos
(7.8-10.7)
13.3 mos
(11.4-14.9)
10.0 mos
(8.4-11.9)
Hazard ratio 0.77
0.020
0.75
0.051
Log rank p-value *
* p-value refers to comparison between arms.

Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. Exploratory demographic analyses showed no apparent differences in patients over or under 65. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination vs. 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 vs. 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.


Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for ALIMTA plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the ALIMTA plus cisplatin arm compared to the control arm.

Patients who received full supplementation with folic acid and vitamin B12 during study therapy received a median of 6 and 4 cycles in the ALIMTA/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the ALIMTA/cisplatin and cisplatin arm, respectively). Patients receiving ALIMTA in the fully supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.

Non-Small Cell Lung Cancer (NSCLC) --The safety and efficacy of ALIMTA as a single-agent have been evaluated in patients with locally advanced or metastatic (Stage III or IV) non-small cell lung cancer after prior chemotherapy.

Randomized Trial: A multi-center, randomized, open label Phase 3 study was conducted to compare the overall survival following treatment with ALIMTA versus docetaxel. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 and docetaxel was administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with ALIMTA received vitamin supplementation with folic acid and vitamin B12. The study was intended to show either an overall survival superiority or non-inferiority of ALIMTA to docetaxel. Patient demographics of the intent to treat (ITT) population are shown in Table 3.

TABLE 3: Summary of Patient Characteristics in
NSCLC study
Patient characteristic ALIMTA
(N=283)
Docetaxel
(N=288)
Age (yrs)
Median (range) 59 (22-81) 57 (28-87)
Gender (%)
Male/Female 68.6/31.4 75.3/24.7
Stage at Entry (%)
III/IV 25.1/74.9 25.3/74.7
Diagnosis/Histology (%)
Adenocarcinoma 154 (54.4) 142 (49.3)
Squamous 78 (27.6) 93 (32.3)
Bronchoalveolar 4 (1.4) 1 (0.3)
Other 51 (18.1) 53 (18.5)
Performance Status (%)
0-1 234 (88.6) 240 (87.6)
2 30 (11.4) 34 (12.4)

The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the ALIMTA treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see Table 4). The study did not show an overall survival superiority of ALIMTA. Non-inferiority of ALIMTA to docetaxel could not be demonstrated, because a reliable and consistent survival effect of docetaxel required for a non-inferiority analysis could not be estimated from historical trials. In addition, significant treatment crossover at the time of disease progression may have confounded the survival interpretation. The demonstrated surrogate endpoint, response rate allowed the conclusion that an effect of ALIMTA on survival is reasonably likely.

Exploratory demographic analyses on survival showed no significant differences between ALIMTA and docetaxel in patients over or under 65 years of age. There were too few non-white patients to assess possible ethnic differences. Regarding gender, females lived longer than males in both treatment groups. There was no difference in survival between ALIMTA and docetaxel with respect to gender after adjusting for prognostic factors.

Secondary endpoints evaluated in the trial include objective response rate, progression free survival (PFS) and time to progressive disease (TTPD). There was no statistically significant difference between ALIMTA and docetaxel with respect to objective response rate, progression free survival (PFS) and time to progressive disease (TTPD).

Table 4: Efficacy of ALIMTA vs. Docetaxel
in Non-Small Cell Lung Cancer - ITT Population
ALIMTA
(N=283)
Docetaxel
(N=288)
Median overall
survival (95% CI) 8.3 mos (7.0-9.4) 7.9 mos (6.3-9.2)
Hazard ratio
(HR) (95% CI) 0.99 a (0.82-1.20)
Log rank p-value 0.93
1-year survival (95% CI) 29.7% (23.7-35.6) 29.7% (23.9-35.5)
Median progression
free survival 2.9 mos 2.9 mos
Hazard ratio
(HR) (95% CI) 0.97 a (0.82-1.16)
Time to Progressive Disease 3.4 mos 3.5 mos
Hazard ratio
(HR) (95% CI) 0.97 a (0.80-1.17)
Overall response
rate a, b (95% CI) 9.1%
(5.9-13.2)
8.8%
(5.7-12.8)
a Not statistically significant.
b Number of qualified patients on the ALIMTA arm (N=264) and docetaxel arm (N=274).

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