DESCRIPTION
MECHANISM OF ACTION
• Pyrrolopyrimidine antifolate analog with activity in the S-phase of the cell cycle.
• Transported into the cell primarily via the RFC and to a smaller extent by the folate-receptor protein (FRP).
• Metabolized intracellularly to higher polyglutamate forms by the enzyme folylpolyglutamate synthase (FPGS). The pentaglutamate form is the
predominant intracellular species. Pemetrexed polyglutamates are approximately 60-fold more potent than the parent monoglutamate compound, and they exhibit prolonged cellular retention.
• Inhibition of the folate-dependent enzyme thymidylate synthase (TS), resulting in inhibition of de novo thymidylate and DNA synthesis. This represents the main site of action of the drug.
• Inhibition of TS leads to accumulation of dUMP and subsequent incorporation of dUTP into DNA, resulting in inhibition of DNA synthesis and function.
• Inhibition of DHFR, resulting in depletion of reduced folates and of critical one-carbon carriers for cellular metabolism.
•Inhibition of de novo purine biosynthesis through inhibition of glycinamide ribonucleotide formyltransferase (GART) and aminoimidazole carboxamide ribonucleotide formyltransferase (AICART)
ABSORPTION
Administered only via the IV route.
DISTRIBUTION
Peak plasma levels are reached in less than 30 minutes. Widely distributed throughout the body. Tissue concentrations highest in liver, kidneys, small intestine, and colon.
INDICATIONS
1. Mesothelioma—FDA-approved in combination with cisplatin for treatment of locally advanced or metastatic non-squamous NSCLC.
2. NSCLC—FDA-approved in combination with cisplatin for the initial treatment of locally advanced or metastatic non-squamous NSCLC.
3. NSCLC—FDA-approved as second-line monotherapy for locally advanced or metastatic non-squamous NSCLC.
4. NSCLC—FDA-approved as maintenance treatment of locally advanced or metastatic non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
5. Pemetrexed should not be used in patients with squamous cell NSCLC.
DOSAGE RANGE
1. Recommended dose as a single agent is 500 mg/m2 IV every 3 weeks.
2. When used in combination with cisplatin, recommended dose is 500 mg/m2 IV every 3 weeks
DRUG INTERACTION 1
Thymidine—Thymidine rescues against the host toxic effects of pemetrexed
DRUG INTERACTION 2
FU—Pemetrexed may enhance the antitumor activity of 5-FU. Precise mechanism of interaction remains unknown.
DRUG INTERACTION 3
Leucovorin—Administration of leucovorin may decrease the antitumor activity of pemetrexed.
DRUG INTERACTION 4
NSAIDs and aspirin—Concomitant administration of NSAIDs and aspirin may inhibit the renal excretion of pemetrexed,
resulting in enhanced drug toxicity.
SPECIAL CONSIDERATIONS
1. Use with caution in patients with abnormal renal function. Important to obtain baseline CrCl and to monitor renal function before each cycle of therapy. Should not be given if CrCl < 45 mL/min.
2. Dose reduction is not necessary in patients with mild or moderate liver impairment.
3. Monitor CBCs on a periodic basis.
4. Use with caution in patients with third-space fluid collections such as pleural effusion and ascites, as the half-life of pemetrexed may be prolonged, leading to enhanced toxicity. Should consider draining of fluid collections prior to initiation of therapy.
5. Dietary folate status of patient is an important factor in determining risk for clinical toxicity. Patients with insufficient folate intake are at increased risk for toxicity. Evaluation of serum homocysteine and folate levels at baseline and during therapy may be helpful. A baseline serum homocysteine level 10 is a good predictor for the development of grade 3/4 toxicities.
6. All patients should receive vitamin supplementation with 350 µg/day of folic acid PO and 1,000 µg of vitamin B12 IM every three cycles to reduce the risk and incidence of toxicity while on drug therapy. Folic acid supplementation should begin 7 days prior to initiation of pemetrexed treatment, and the first vitamin B12 injection should be administered at least 1 week prior to the start of pemetrexed. No evidence has been found to suggest that vitamin supplementation reduces clinical efficacy.
7. Prophylactic use of steroids may ameliorate and/or completely eliminate the development of skin rash. Dexamethasone can be given at a dose of 4 mg PO bid for 3 days beginning the day before therapy.
8. NSAIDs and aspirin should be discontinued for at least 2 days before therapy with pemetrexed and should not be restarted for at least 2 days after a drug dose. These agents may inhibit the renal clearance of pemetrexed, resulting in enhanced toxicity.
9. Pregnancy category D. Breastfeeding should be avoided.
TOXICITY 1
Myelosuppression. Dose-limiting, dose-related toxicity, with neutropenia and thrombocytopenia being most commonly observed.
TOXICITY 2
Skin rash, usually in the form of the hand-foot syndrome.
TOXICITY 3
Mucositis, diarrhea, and nausea and vomiting.
TOXICITY 4
Transient elevation in serum transaminases and bilirubin. Occurs in 10%–15% of patients. Clinically asymptomatic in most cases.
TOXICITY 5
Fatigue.
SPECIFICATION
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