Pemetrexed

Pemetrexed (brand name Alimta) is a chemotherapy drug manufactured and marketed by Eli Lilly and Company. Its indications are the treatment of pleural mesothelioma and non-small cell lung cancer.

History

The molecular structure of pemetrexed was developed by Edward C. Taylor at Princeton University and clinically developed by Indianapolis based drug maker, Eli Lilly and Company in 2004.

It has been researched in the PARAMOUNT trial.

Mechanism of action

Pemetrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). By inhibiting the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.

File:Pathway of tetrahydrofolate and antimetabolites.pdf

Clinical use

In February 2004, the Food and Drug Administration approved pemetrexed for treatment of malignant pleural mesothelioma, a type of tumor of the lining of the lung, in combination with cisplatin for patients whose disease is either unresectable or who are not otherwise candidates for curative surgery. In September 2008, the FDA granted approval as a first-line treatment, in combination with cisplatin, against locally-advanced and metastatic non-small cell lung cancer (NSCLC) in patients with non-squamous histology. A Phase III study showed benefits of maintenance use of pemetrexed for non-squamous NSCLC. Activity has been shown in malignant peritoneal mesothelioma. Trials are currently testing it against esophagus and other cancers.

Carboplatin

Pemetrexed is also recommended in combination with carboplatin for the first-line treatment of advanced non-small cell lung cancer. However, the relative efficacy or toxicity of pemetrexed-cisplatin versus pemetrexed-carboplatin has not been established beyond what is generally thought about cisplatin or carboplatin doublet drug therapy

Supplementation

Patients should take folic acid and vitamin B₁₂ supplement even if levels are normal when they are on pemetrexed therapy. (In clinical trials for mesothelioma, folic acid and B12 supplementation reduced the frequency of adverse events.) It is also recommended for patients to be on a steroid (e.g., dexamethasone 4 mg twice daily) on the day prior, day of, and day after Pemetrexed infusion to avoid skin rashes.

Side effects

Pemetrexed, whether used alone or in combination with cisplatin, has these side effects:

• Low blood cell counts, as measured by a complete blood count. This is a dose-limiting toxicity.
• Mental fatigue and sleepiness. Fatigure can be reduced through an off-label prescription of Provigil.
• Nausea and vomiting. Pemetrexed's emetogenic effects are managed with prophylactic antiemetics.
• Diarrhea
• Oral mucositis (mouth, throat, or lip sores). Oral ulcers can be mitigated by proper oral hygiene, including rinsing of the mouth with salt water following consumption of food or drink.
• Loss of appetite
• Skin rash. Physician-prescribed steroids administered on the day prior, day of, and day after infusion typically avoid skin rashes.
• Constipation

Trade names

In addition to the brand name Alimta, this drug is also marketed in India by Abbott Healthcare as Pleumet and by Cadila Healthcare as Pemecad.

External links

• Alimta website
• NCI Drug Information Summary on Pemetrexed Disodium