Pemetrexed (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pemetrexed Injection is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as 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.

12.2 Pharmacodynamics

Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12 . There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

12.3 Pharmacokinetics

The pharmacokinetics of pemetrexed were evaluated in patients with cancer at doses ranging from 0.2 to 838 mg/m2 [0.0004 to 1.7 times the recommended dosage] infused over a 10-minutes. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax ) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.

Distribution

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro pemetrexed is 81% bound to plasma proteins.

Elimination

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). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases.

Metabolism

Pemetrexed is not metabolized to an appreciable extent.

Excretion

Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed.

Specific Populations

Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses.

Racial Groups

The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups.

Patients with Hepatic Impairment

Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies.

Patients with Renal Impairment

Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

Third-Space Fluid

The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known.

Drug Interaction Studies

Drugs Inhibiting OAT3 Transporter

Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min).

In Vitro Studies

Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu ]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent [see Drug Interactions (7)].

Pemetrexed is a substrate for OAT4. In vitro , ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations.

Aspirin

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed.

Vitamins

Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes

In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay).

Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

14 CLINICAL STUDIES

14.1 Non-Squamous NSCLC

Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B12 , and dexamethasone [see Dosage and Administration (2.3)]. Randomization was carried out using a minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN.

A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies.

Efficacy results are presented in Table 5 and Figure 1.

Table 5: Efficacy Results in Study JMEN

Efficacy Parameter

Pemetrexed

Placebo

Overall survival

N=441

N=222

Median (months)

13.4

10.6

(95% CI)

(11.9-15.9)

(8.7-12.0)

Hazard ratioa

0.79

(95% CI)

(0.65-0.95)

p-value

p=0.012

Progression-free survival per independent review

N=387

N=194

Median (months)

4.0

2.0

(95% CI)

(3.1-4.4)

(1.5-2.8)

Hazard ratioa

0.60

(95% CI)

(0.49-0.73)

p-value

p<0.00001

a Hazard ratios are adjusted for multiplicity but not for stratification variables.

Figure 1: Kaplan-Meier Curves for Overall Survival in Study JMEN

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The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 6 and Figures 2 and 3.

Table 6: Efficacy Results in Study JMEN by Histologic Subgroup

Efficacy Parameter

Overall Survival

Progression-Free Survival

Per Independent Review

Pemetrexed

(N=441)

Placebo

(N=222)

Pemetrexed

(N=387)

Placebo

(N=194)

Non-squamous NSCLC (n=481)

Median (months)

15.5

10.3

4.4

1.8

HRa

0.70

0.47

(95% CI)

(0.56 to 0.88)

(0.37 to 0.60)

Adenocarcinoma (n=328)

Median (months)

16.8

11.5

4.6

2.7

HRa

0.73

0.51

(95% CI)

(0.56 to 0.96)

(0.38 to 0.68)

Large cell carcinoma (n=20)

Median (months)

8.4

7.9

4.5

1.5

HRa

0.98

0.40

(95% CI)

(0.36 to 2.65)

(0.12 to 1.29)

Otherb (n=133)

Median (months)

11.3

7.7

4.1

1.6

HRa

0.61

0.44

(95% CI)

(0.40 to 0.94)

(0.28 to 0.68)

Squamous cell NSCLC (n=182)

Median (months)

9.9

10.8

2.4

2.5

HRa

1.07

1.03

(95% CI)

(0.77 to 1.50)

(0.71 to 1.49)

a Hazard ratios are not adjusted for multiplicity

b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.

Figure 2: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN

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Figure 3: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMEN

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Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with platinum-based first-line chemotherapy and achieved a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed in combination with platinum-based first-line chemotherapy induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B12 , and dexamethasone. The main efficacy outcome measure was investigator-assessed progression- free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization.

A total of 539 patients were enrolled with 359 patients randomized to pemetrexed and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies.

Efficacy results for PARAMOUNT are presented in Table 7 and Figure 4.

Table 7: Efficacy Results in PARAMOUNT

Efficacy Parameter

Pemetrexed (N=359)

Placebo

(N=180)

Overall survival

Median (months)

13.9

11.0

(95% CI)

(12.8 to 16.0)

(10.0 to 12.5)

Hazard ratio (HR)a

0.78

(95% CI)

(0.64 to 0.96)

p-value

p=0.02

Progression-free survivalb

Median (months)

4.1

2.8

(95% CI)

(3.2 to 4.6)

(2.6 to 3.1)

Hazard ratio (HR)a

0.62

(95% CI)

(0.49 to 0.79)

p-value

p<0.0001

a Hazard ratios are adjusted for multiplicity but not for stratification variables.

b Based on investigator’s assessment.

Figure 4: Kaplan-Meier Curves for Overall Survival in PARAMOUNT

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Treatment of Recurrent Disease After Prior Chemotherapy

The efficacy of pemetrexed was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed also received folic acid and vitamin B12 . The study was designed to show that overall survival with pemetrexed was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure.

A total of 571 patients were enrolled with 283 patients randomized to pemetrexed and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of 0 or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC.

The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 8 and 9, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of a treatment effect on survival in patients with squamous NSCLC; the absence of a treatment effect in patients with NSCLC of squamous histology was also observed Studies JMEN [see Clinical Studies (14.1)].

Table 8: Efficacy Results in Study JMEI

Efficacy Parameter

Pemetrexed

(N=283)

Docetaxel

(N=288)

Overall survival

Median (months)

8.3

7.9

(95% CI)

(7.0 to 9.4)

(6.3 to 9.2)

Hazard ratioa

0.99

(95% CI)

(0.82 to 1.20)

Progression-free survival

Median (months)

2.9

2.9

(95% CI)

(2.4 to 3.1)

(2.7 to 3.4)

Hazard ratioa

0.97

(95% CI)

(0.82 to 1.16)

Overall response rate

8.5%

8.3%

(95% CI)

(5.2 to 11.7)

(5.1 to 11.5)

a Hazard ratios are not adjusted for multiplicity or for stratification variables.

Table 9: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI

Histologic Subgroups

Pemetrexed

(N=283)

Docetaxel

(N=288)

Non-squamous NSCLC (N=399)

Median (months)

9.3

8.0

(95% CI)

(7.8 to 9.7)

(6.3 to 9.3)

HRa

0.89

(95% CI)

(0.71 to 1.13)

Adenocarcinoma (N=301)

Median (months)

9.0

9.2

(95% CI)

(7.6 to 9.6)

(7.5 to 11.3)

HRa

1.09

(95% CI)

(0.83 to 1.44)

Large Cell (N=47)

Median (months)

12.8

4.5

(95% CI)

(5.8 to 14.0)

(2.3 to 9.1)

HRa

0.38

(95% CI)

(0.18 to 0.78)

Otherb (N=51)

Median (months)

9.4

7.9

(95% CI)

(6.0 to 10.1)

(4.0 to 8.9)

HRa

0.62

(95% CI)

(0.32 to 1.23)

Squamous NSCLC (N=172)

Median (months)

6.2

7.4

(95% CI)

(4.9 to 8.0)

(5.6 to 9.5)

HRa

1.32

(95% CI)

(0.93 to 1.86)

a Hazard ratio unadjusted for multiple comparisons.

b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.


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