Pemetrexed (Alimta™) is a new analogue of folic acid with a powerful inhibiting activity of thymidylate synthetase but also for other enzymes which interfere with the synthesis of pyrimidic and puric bases.
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One of the first targets (as in methotrexate) is thymidylate synthetase which catalyses the transformation of dUMP into DTMP, thus reducing the quantity of thymidine to be used for DNA synthesis.
Two other enzymes, involved in the synthesis of puric bases, are modified through pemetrexed: aminoimidazole carboxamide ribonucleotide transformylase (GAFRT) and glycinamide ribonucleotide transformylase. The competition between these two enzymes explains the activity of pemetrexed on cell lines resistant to ralitrexed or to 5-FU (see diagram below).
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The main indication in 2005 was:
mesothelioma: permetrexed offered an increased survival of 4 months in association with cisplatin among patients for whom no therapy had hitherto been available.
.However numerous phase II and phase III studies are in progress.
The usual dosage is 500 mg/m2 , to be repeated every 3 weeks, under usual hemogram monitoring
Current studies aim at determining if permetrexed dosage may be increased under cover of an association with folinic acid (as for methorexate).
Only specific toxicities (or major toxicities) are described here. Other common chemotherapy toxicities are described in the chapter on chemotherapy toxicity.
Deficiency in folate and vitamin B12
Some very acute toxicities have been described with either major myelosuppresion or major digestive toxicity.
These disorders appear to be related to a pre-existing deficiency in folate or vitamin B-12 which should be detected before treatment (by the measurement of blood homocysteine which is increased over 10μM in the case of major deficiency).
In order to avoid an unnecessary risk, patients are systematically administered an oral dose of 350 to 1,000 µg of folic acid and an IM dose oμg of folic acid and a IM dose of 1,200 μg of vitamin B12, during the 5 first days of treatment and regularly repeated thereafter.