Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment
ATC Code: V03AF04
Levofolinate is the pharmacologically active isomer of 5-formyltetrahydrofolic acid. Levofolinate does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilising folates as a source of “one carbon” moieties. Levofolinate is actively and passively transported across cell membranes.
Administration of levofolinate can “rescue” normal cells and thereby prevent toxicity of folic acid antagonists such as methotrexate which act by inhibiting dihydrofolate reductase. Levofolinate can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolised to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FDUMP), which binds to and inhibits thymidylate synthase. Levofolinate is readily converted to another reduced folate, 5, 10-methylenetetrahydrofolate, which acts to stabilise the binding of FDUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme.
Levofolinate is also effective in the treatment of megaloblastic anaemias due to folate deficiencies.
When levofolinate is injected intravenously it is 100% bioavailable.
The pharmacokinetics of levofolinate after intravenous administration of a 15 mg dose were studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/ml. Serum levo-5-methyl-THF concentrations reached a mean peak of 275 ng/ml and the mean time to peak concentration was 0.9 hours. The mean half-life for total-THF and levo-5-methyl-THF was 5.1 and 6.8 hours respectively.
The distribution and plasma levels of levofolinate following intramuscular administration have not been established.
The distribution in tissue and body fluids and protein binding have not been determined.
In vivo, levofolinate is converted to levo-5-methyltetrahydrofolic acid (levo-5-methyl-THF), the primary circulating form of active reduced folate. Levofolinate and levo-5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.
Levofolinate and levo-5-methyl-THF are excreted renally.
Due to the inherent lack of levofolinate toxicity, the influence of impaired renal or hepatic function on levofolinate disposition was not evaluated.
The pre-clinical data raises no concerns for the clinical uses indicated.
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