Pemetrexed disodium (Alimta)

Folate antimetabolite that inhibits thymidylate synthetase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase resulting in depletion of reduced folate and disruption of nucleotide synthesis.

A multitargeted antifolate that inhibits several folate-dependent enzymes involved in purine and pyrimidine synthesis.

A multitargeted antimetabolite that inhibits thymidylate synthetase, and to a lesser extent, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, which are involved in the de novo synthesis of purines and/or pyrimidines (Hanna N).

Differs from methotrexate by having a pyrollopyrimidine based core instead of a pteridine ring which is in methotrexate and folate.

Transported into cells by the reduced folate carrier system as is methotrexate.

Folic acid supplementation significantly reduces side effects of the drug.

Side effects include neutropenia, thrombocytopenia, anemia, asthenia, rash, anorexia, nausea, vomiting, mucositis, edema, diarrhea, transient transaminase and creatinine elevation.

Folic acid 350-1000 microgm daily should be started 1-3 weeks before the first dose of pemetrexed and continues while on treatment.

B12 1000 microgm injections should be started 1-3 weeks before the first does of chemotherapy and repeated every 9 weeks while on treated.

The addition of steroid to the treatment reduces the risk of rash.

Elevated plasma homocysteine levels, a marker for folic acid and B12 deficiency, predict for thrombocytopenia, neutropenia, diarrhea, mucositis and infection in patients treated with pemetrexed.

Elevated methylmalonic acid, a marker for B12 deficiency, predicts for diarrhea and mucositis toxicity in patients treated with pemetrexed.

Eliminated in the urine with 70-90% recovered unchanged within the first 24 hours.

In combination with cis-platinum leads to a median survival time of 12.1 months for malignant pleural mesothelioma.

And docetaxel produce similar response rates in second line treatment of non small cell lung cancer with much less toxicity in pemetrexed treated group.

Has significant activity against nonsquamous NSCLC, but minimal activity against squamous cell NSCLC.

Phase II studies as first time treatment for advanced NSCLC produced overall response rates of 15.8-23.3%, with median survival of 7.2-9.2 months with 1 year survival rates of 25-32%.

Phase I combination treatments with pemetrexed and cisplatin in first line treatment of advanced NSCLC have response rates 38.9-44.8% with a median survival of 8.9-10.9 months and a median survival at 1 year 50%.

Significant activity in mesothelioma, NSCCL, breast cancer, colorectal cancer, bladder, cervical, esophageal, head and neck, ovarian, pancreatic, renal cell cancer and gastric cancer.

In combination with carboplatin has a similar median survival of gemcitabine and carboplatin in advanced NSCLC 7.3 vs 7.0 months, respectively (Grenberg B).

In a phase III study a maintenance pemetrexed plus best supportive care versus placebo immediately following induction therapy with pemetrexed plus cisplatin for advanced non-small cell lung cancer (PARAMOUNT) study: Pemetrexed maintenance has improved clinical benefit with a 36% reduction in the risk of progression.

In advanced bladder cancer 500 mg/m2 every three weeks was associated with a overall response rate of 28% and the median time to progression of 2.9 months and overall survival of 9.6 months. (Hoosier Oncology Group).

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