Brand name: ALIMTA™
Generic name: Permetrexed
Manufacturer: Eli Lilly and Company
Drug Class: Antineoplastic agents; Antimetabolites; Antifolates
Uses:
Labeled: Used in combination with cisplatin for the treatment of malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for curative surgery.
Permetrexed has been submitted for FDA approval for use as a single-agent, second-line treatment for non-small-cell lung cancer.
Currently being evaluated for use in the treatment of bladder cancer, breast cancer, non-Hodgkin’s lymphoma, and pancreatic cancer
Mechanism of Action:
Pemetrexed is an antifolate, and is able to inhibit several enzymes involved in folate metabolism and DNA synthesis.1
Following cellular uptake, pemetrexed undergoes polyglutamation to form triglutamates and pentaglutamates (the predominant form and more potent). Polyglutamation results in prolonged intracellular retention of the active compound and increases potency against the target enzymes.2 Pemetrexed and its polyglutamtates inhibit thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyl transferase, and aminoimidazole carboxamide ribomucleotide formyltransferase.1,2,3 Pyrimidine and purine pathways are inhibited.1
Additive or greater activity has been observed in xenografts which were exposed to pemetrexed in conjunction with 5-fluorouracil, methotrexate, vinorelbine, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, doxorubicin, and paclitaxel.6 When gemcitabine exposure occurred prior to pemetrexed in vitro, synergistic activity was observed, however when pemetrexed preceded an antagonistic interaction was observed.1,4
Pharmacokinetics:
Pharmacokinetic profile following administration of pemetrexed disodium 600mg/m2 as a 10-minute intravenous infusion every 21day1,12,13,14:
|
Volume of Distribution (Vd) |
6-9.9L/m2 |
|
Clearance (Cl) |
40-55 mL/min/ m2 (dependent on creatinine clearance and folate deficiency) |
|
Half-life (t1/2) |
3 hours |
Permetrexed is primarily eliminated as unchanged drug in the urine (70%-90% of the dose).12,13
Clearance is reduced in subjects with reduced renal function and in patients with folate deficiency. The 600mg/m2 dose administered every 21 days was tolerated in patients with a GFR of 80ml/min or greater. A 500mg/m2 dose every 21 days was tolerated in patients with mild renal impairment (GFR 40ml/min).14
Efficacy:
Permetrexed disodium has been evaluated in several Phase II studies; Phase III studies are currently ongoing.
In an open-label Phase II study, pemetrexed was evaluated in 33 chemotherapy-naïve patients with unresectable advanced non-small-cell lung cancer. Patient received 600mg/m2 every 3 weeks initially (dose was decreased to 500mg/m2 after toxicity was observed). Patient received up to four cycles after complete or partial remission or six cycles after stable disease was documented. The overall response rate was 23.3%, with the median duration of response at 3.1 months. Response was observed in 4 of 6 patients (67%) with stage IIIB disease compared to 3 of 24 (12.5%) with stage IV disease. The median time to progression for all patients was 3.8 months, and the median survival time of all patients was 9.2 months. Survival rate at 1 year was 25.3%.16,28
Pemetrexed was evaluated in conjunction with cisplatin therapy in a Phase II study enrolling 36 chemotherapy-naive patients with non-small-cell lung cancer. The patients received pemetrexed 500mg/m2 plus cisplatin 75mg/m2 every 21 days. Dexamethasone 4mg twice daily was administered the day before, the day of, and the day after pemetrexed. A partial response was received in 14 patients (39%). 33% of patients remained progression free at 12 months. Median survival was 10.9 months with the probability of surviving at 50%.9
Pemetrexed was also evaluated in other Phase II studies:
Colorectal Cancer who had not received prior chemotherapy for metastatic disease: Dose 600mg/m2 every 21 days, then dose reduced to 500mg/m2. Among 29 patients, only 1 patient had complete response and 4 patients had a partial response (response rate 17.2%). Median overall survival was 15.1 months, and median time to disease progression was 3.3 months.18
Unresectable or metastatic pancreatic cancer: 600mg/m2 every 21 days. One complete response and one partial response were achieved among the 36 patients (response rate 5.7%) The median survival was 6.5 months, with 28% of patients alive at 1 year.19
Metastatic breast cancer: 600mg/m2 every 21 days. One complete response and nine partial responses were achieved in the 36 patients studied (response rate 28%). Median duration of response was 8 months and median survival was 13 months.20
Additional Phase II studies are assessing pemetrexed in patients with bladder, esophageal, renal cell, head and neck, and cervical cancers.4
Adverse Effects:
Adverse effects include neutropenia, thrombocytopenia, fatique, maculopapular rash, mucositis, nausea, vomiting, anorexia, diarrhea, constipation, fever, and elevations of liver transaminases.1,15,16,18,20,24
The rash is erythematous, typically involving the face and trunk, sometimes being painful. Administration of dexamethasone improved or prevented rash during cycles.1,2,18
Clinically asymptomatic elevations of ALT, AST, alkaline phosphatase, and gamma-glutamyl transferase have been observed. Nausea and vomiting have been treated and managed with antiemetics.15
Contraindications, Warnings, Precautions:
The dose-limiting toxicities of pemetrexed are neutropenia, thrombocytopenia, and fatique.
Maximum tolerated dose is 600mg/m2 every 21 days, 40mg/m2 administered once a week for 4 consecutive weeks, or 4mg/ m2 as a daily dose for 5 days repeated every 21 days.1,13,24,25
Gemcitabine and pemetrexed- neutropenia is the dose-limiting toxicity
Cisplatin and pemetrexed- leukopenia/neutropenia and fatique were the dose-limiting toxicities.28
Dexamethasone has been administered with pemetrexed to reduce incidence of severe rash.
Folic acid 350-100mcg dialy or 5 mg daily on days –2 to +2 of each cycle and vitamin B12 1000mcg IM every 9 weeks have been added to the pemetrexed to reduce toxicity.3,8,21,26,28
Administration of folic acid and vitamin B12 reduced the incidence of of drug-related death, severe neutropenia, thrombocytopenia, diarrhea, mucositis, and overall sever hematologic and nonhematologic toxicities (specifically G3/G4 hematologic or nonhematologic toxicity).28
Pregnancy Category D
Drug Interactions:
Administration with cisplatin and its associated hydration regimen resulted in an increased pemetrexed total plasma clearance and volume of distribution at steady state. Half-life was unchanged.2
Dosing:
Based on results of Phase I studies and Phase II studies, doses were 500mg/m2 or 600mg/m2 every 21 days.1
Renal Failure: most of the intravenous dose is excreted unchanged in the urine, and dose modification is indicated in renal impairment. Specific guidelines have not been established.14 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 in clinical trials.28
Dosing in patient with a creatinine clearance <45ml/min have not been studied and therefore not recommended.14
Geriatric: The dose of pemetrexed is reduced in elderly patients probably related to declining renal function.14
Conclusions:
Pemetrexed is a new antineoplastic agent with a slightly different mechanism than other currently available antimetabolite antineoplastics. It has demonstrated activity in several cancers and is currently being evaluated for use in these conditions with other chemotherapeutic agents.
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