Medical Pharmacology Chapter 33-34: Anticancer Drugs
Antifolate Analogues: Pemetrexed (Alimta)
Pemetrexed (Alimta) is another example of an antifolate antineoplastic drug.7
This agent is a thymidylate synthase (TS) inhibitor and also inhibits
Dihydrofolate reductase (DHFR)
Glycinamide ribonucleotide formyltransferase (GARFT)
Aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT).
These enzymes are involved both in DNA synthesis and folate metabolism.
Inhibition of these enzymes cause inhibition of purine and thymidine nucleotide and protein synthesis.
As described earlier for methotrexate, pemetrexed is taken into the cells using transport systems including reduce folate carriers and membrane folate binding protein transporters.8
Following transport, intracellularly, permetrexed, like methotrexate, is converted to polyglutamate forms depending on enzymic catalysis by folylpolyglutamate synthase.
By ion trapping mechanisms discussed earlier, these polyglutamate forms are concentrated in cells where they inhibit TS (thymidylate synthase) and GARFT (glycinamide ribonucleotide formyltransferase).
Polyglutamated metabolites appear to extend active drug intracellular half-life, thus extending drug efficacy in malignant cells.8
Similar to methotrexate, permetrexed is eliminated principally by the kidneys.
Assuming normal renal function, the t1/2 of elimination is about 3.5 hours.7
Pemetrexed exhibits comparable toxicities to that noted with methotrexate.1
However, pemetrexed is associated with an additional toxicity, a significant erythematous and pruritic rash affecting nearly half of patients.
This toxicity can be mitigated with dexamethasone.
In some patients, unpredictably, pemetrexed may induce a severe myelosupression, most likely seen in patients who have preexisting homocystinemia.1
This reaction is mainly eliminated by kind current low-dose folic acid administration beginning 1 or 2 weeks prior to pemetrexed administration with low-dose folic acid administration continuing during pemetrexed administration.
As an aside, patients should likely receive, intramuscularly, vitamin B12 accompanying the first pemetrexed dose.
Vitamin B12 would be administered to correct a possible pre-existing B12 deficiency.1
With respect to labeled indications, permetrexed is appropriate as initial treatment of malignant pleural mesothelioma and is administered in combination with cisplatin in those cases in which disease is either unresectable or in patients not considered eligible for curative surgery.
Permetrexed is also used as initial treatment for locally advanced as well as metastatic nonsquamous non-small cell lung cancer (NSCLC), again in combination with cisplatin.
It is also used in treating metastatic, nonsquamous NSCLC, given in combination with carboplatin and pembrolizumab.
Pemetrexed as single-agent treatment may be used as maintenance therapy for locally advanced or metastatic nonsquamous NSCLC in absence of progression following 4 cycles of a platinum-based first-line treatment.
Pemetrexed is also considered a single-agent treatment following
prior chemotherapy in cases of recurrent or metastatic nonsquamous