Pemetrexed

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[edit] BRAND NAMES

[edit] STRUCTURE

File:Pemetrexed.jpg

[edit] MECHANISM OF ACTION

Pemetrexed, is a cytotoxic medicine, which belongs to the group antimetabolites. In the body, Pemetrexed is converted into an active form that blocks the activity of the enzymes that are involved in producing nucleotides (the building blocks of DNA and RNA, the genetic material of cells). As a result, the active form of Pemetrexed slows down the formation of DNA and RNA and prevents the cells from dividing and multiplying. The conversion of pemetrexed into its active form occurs more readily in cancer cells than in normal cells, leading to higher levels of the active form of the medicine and a longer duration of action in cancer cells. This results in the division of cancer cells being reduced, while normal cells are only slightly affected.

More specifically, Pemetrexed acts as a folate analog metabolic inhibitor, exerting its action by disrupting folate dependent metabolic processes essential for cell replication. It inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), 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. Polyglutamation occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

[edit] INDICATIONS

Pemetrexed is used to treat two types of lung cancer:

  • Malignant pleural mesothelioma (a cancer of the lining of the lungs that is usually caused by exposure to asbestos), where it is used together with cisplatin in patients who have not received chemotherapy before and whose cancer cannot be removed by surgery. Patients receiving Pemetrexed and cisplatin survived for an average of 12.1 months, compared with 9.3 months in those receiving cisplatin alone.
  • Advanced non small cell lung cancer of the kind known as non-squamous, where it is used either in combination with cisplatin in previously untreated patients or on its own in patients who have previously received anticancer treatment. It can also be used as a maintenance treatment in patients who have received a platinum-based chemotherapy. Pemetrexed was as effective as the comparators, with survival times around 10.3 months in patients who had not received chemotherapy in the past, and around 8.1 months in those who had received chemotherapy in the past. In one maintenance treatment study, patients receiving Pemetrexed lived for a further 4.3 months from the start of maintenance treatment without their cancer getting worse, compared with 2.6 months in those receiving placebo. In the second maintenance study, the figures were 4.1 months in the Pemetrexed and 2.8 months in the placebo group

[edit] DOSAGE

The recommended dose of Pemetrexed is 500 mg/m2 of body surface area (calculated using the patient’s height and weight). It is given once every three weeks as an infusion lasting 10 minutes.

To reduce side effects, patients should take a dexamethasone (4 mg by mouth twice daily the day before, the day of, and the day after Pemetrexed administration) and folic acid (Initiate with 400-1000 mcg orally once daily beginning 7 days before the first dose of Pemetrexed), and receive injections of vitamin B12 during treatment (1 mg intramuscularly 1 week prior to the first dose of Pemetrexed and every 3 cycles thereafter)

When Pemetrexed is given with cisplatin, an ‘anti emetic’ medicine (to prevent vomiting) and fluids (to prevent dehydration) should also be given before or after the cisplatin dose.

Treatment should be delayed or stopped, or the dose reduced, in patients whose blood counts are abnormal or who have certain other side effects

[edit] DOSAGE FORMS AND STRENGTHS

  • 100 mg vial for injection
  • 500 mg vial for injection

[edit] CONTRAINDICATIONS

  • History of severe hypersensitivity reaction to pemetrexed

[edit] PRECAUTIONS

  • Premedication regimen: Prior to treatment with Pemetrexed, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity.
  • Bone marrow suppression: Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.
  • Renal function: Do not administer when CrCl <45 mL/min.
  • NSAIDs with renal insufficiency: Use caution when administering Pemetrexed concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min
  • Lab monitoring: Do not initiate a cycle unless absolute neutrophil count (ANC) ≥1500 cells/mm3, platelets ≥100,000 cells/mm3, and CrCl ≥45 mL/min.

[edit] INTERACTIONS

[edit] PREGNANCY AND LACTATION

  • Pregnancy Category D (US). Fetal harm can occur when administered to a pregnant woman. Women should be advised to use effective contraception measures to prevent pregnancy during treatment with Pemetrexed

[edit] SIDE EFFECTS

The most common side effects are bone marrow suppression and gastrointestinal toxicities. Bone marrow suppression causes decreased levels in the blood of white blood cells, platelets and haemoglobin. The gastrointestinal toxicities seen with Pemetrexed are loss of appetite, nausea, vomiting, diarrhea, constipation, pharyngitis, and mucositis or stomatitis.

[edit] RELATED LINKS

[edit] BIBLIOGRAPHY

[edit] REFERENCES