What is Leucovorin (folinic acid)?

Leucovorin (Folinic Acid): Clinical Overview

Leucovorin (folinic acid) is a reduced folate derivative that serves as an antidote to folic acid antagonists and enhances the therapeutic effects of fluoropyrimidines in cancer therapy. It is also known as Citrovorum factor or 5-formyl-5,6,7,8-tetrahydrofolic acid 1.

Chemical Structure and Properties

• Leucovorin calcium has the chemical designation of Calcium N-[p-[[[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1) 1
• It is a mixture of diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF), with the biologically active compound being the (-)-I-isomer 1
• Unlike folic acid, leucovorin does not require reduction by the enzyme dihydrofolate reductase to participate in one-carbon transfer reactions 1

Pharmacokinetics

• After intravenous administration, serum total reduced folates reach a mean peak of 1,259 ng/mL at approximately 10 minutes 1
• The initial rise in total reduced folates is primarily due to the parent compound 5-formyl-THF 1
• The active metabolite 5-methyl-THF becomes the predominant circulating form with a mean peak of 258 ng/mL occurring at 1.3 hours 1
• The terminal half-life for total reduced folates is approximately 6.2 hours 1

Clinical Applications

1. Methotrexate Toxicity Management

• Leucovorin is used as rescue therapy for methotrexate toxicity by bypassing the inhibition of dihydrofolate reductase 1, 2
• For patients receiving intrathecal methotrexate, oral leucovorin (10 mg) may be administered twice daily beginning on the day of treatment and continuing for 3 days to mitigate systemic toxicity 2
• In severe low-dose methotrexate toxicity, doses of 15-25 mg every 6 hours have been used, with no significant difference in outcomes between these dosing regimens 3
• For high-dose methotrexate toxicity, leucovorin can be used as sole therapy with doses varying from 0.24 to 8 g/day, depending on methotrexate levels 4

2. Cancer Treatment

• Leucovorin enhances the therapeutic and toxic effects of fluoropyrimidines such as 5-fluorouracil by stabilizing the binding of fluorodeoxyridylic acid to thymidylate synthase 1
• It is a key component in several chemotherapy regimens for colorectal cancer:
  • FOLFOX: Leucovorin (400 mg/m²) combined with oxaliplatin and 5-fluorouracil 5
  • FOLFIRI: Leucovorin (400 mg/m²) combined with irinotecan and 5-fluorouracil 5
  • Simplified biweekly infusional 5-FU/leucovorin (sLV5FU2): Leucovorin (400 mg/m²) followed by 5-FU bolus and continuous infusion 5
  • Roswell-Park regimen: Leucovorin (500 mg/m²) with 5-FU 5

3. Autism Spectrum Disorder

• Leucovorin is being investigated for use in children with autism and elevated B12 levels to bypass potential folate metabolism issues 6
• It may be more bioavailable to the brain than folic acid as it doesn't require the same metabolic conversion 6
• Starting doses of approximately 5 mg/day are recommended, with gradual increases while monitoring for side effects 6

Dosing Considerations

• Leucovorin 400 mg/m² is equivalent to levo-leucovorin 200 mg/m² 5
• The pure l-FA form (levo-leucovorin) and the racemic mixture (d,l-FA) show comparable blood profiles of active folates and similar treatment tolerance 7
• Dosing for methotrexate rescue should be based on methotrexate plasma concentrations, with various methods including empirical calculations and nomograms 8

Protective Effects

• Folinic acid provides protection against methotrexate-induced genetic damage in both animal models and humans 9
• Preventive folic acid supplementation (1 mg/day) is recommended for patients on regular methotrexate therapy to reduce adverse effects, but leucovorin is preferred for acute rescue 2

Clinical Considerations

• Patients with renal insufficiency require special attention when using methotrexate with leucovorin rescue 2
• Regular monitoring of complete blood count, liver function tests, and renal function tests is essential during methotrexate therapy to detect early signs of toxicity 2
• Leucovorin calcium for injection is available in 200 mg vials, which when reconstituted with 20 mL of sterile diluent, contains 10 mg/mL 1

Leucovorin's ability to both rescue from methotrexate toxicity and enhance fluoropyrimidine efficacy makes it an essential medication in oncology practice and other clinical settings.