Folate Antagonists

Folate antagonists inhibit enzymes of folate metabolism needed for thymidylate and purine synthesis. Methotrexate inhibits dihydrofolate reductase; pemetrexed inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase; raltitrexed inhibits thymidylate synthase; pralatrexate is a dihydrofolate reductase inhibitor with high uptake in T-cell lymphoma.

Classification. Methotrexate, pemetrexed, raltitrexed, pralatrexate.

Pharmacokinetics. Methotrexate is eliminated by the kidney (80 to 90 percent unchanged within 24 hours) through filtration and secretion, so impaired kidney function prolongs exposure. It distributes into third-space fluid (pleural effusion, ascites), which acts as a reservoir.

• Methotrexate, low dose oncological: 20 to 40 mg/m2 weekly orally or intramuscularly; intermediate 500 mg/m2 to 1 g/m2; high dose 3 to 12 g/m2 over 4 to 24 hours; intrathecal 12 mg (age-based in children).
• Folinic acid rescue 15 mg intravenously or orally every 6 hours, starting 24 hours after the start of a high-dose methotrexate infusion and continued until the methotrexate level is under 0.05 micromol/L (higher doses of folinic acid if the level is high).
• Glucarpidase for delayed elimination with kidney injury and a very high methotrexate level.
• Pemetrexed 500 mg/m2 over 10 minutes every 3 weeks, with folic acid 400 microgram daily starting 7 days before the first dose and continued 21 days after the last dose, vitamin B12 1,000 microgram intramuscularly 1 week before the first dose and then every 9 weeks, and dexamethasone 4 mg twice daily for 3 days around each dose.
• Raltitrexed 3 mg/m2 every 3 weeks.

Differences. Methotrexate needs leucovorin rescue at high dose; pemetrexed needs vitamin supplementation to prevent toxicity.

• High-dose methotrexate: osteosarcoma, acute lymphoblastic leukaemia, central nervous system lymphoma. Needs hydration (3 litres/m2 daily), urine alkalinisation to pH 7.0 or more, and daily level monitoring until the level is safe.
• Intrathecal methotrexate: prophylaxis and treatment of meningeal leukaemia or lymphoma.
• Pemetrexed: non-squamous non-small cell lung cancer and mesothelioma.
• Hospital checks before each high-dose cycle: creatinine clearance over 60 mL/min (pemetrexed over 45 mL/min), no third-space fluid, liver function and urine pH.
• Drug avoidance: omit penicillins, NSAIDs, proton pump inhibitors, co-trimoxazole, ciprofloxacin and probenecid for the days around methotrexate.

Selection. Use pemetrexed only after confirming non-squamous histology; high-dose methotrexate should be given only where levels can be measured daily.

Contraindications. Pregnancy; creatinine clearance under 45 mL/min for pemetrexed; significant effusions or ascites without drainage; severe liver failure.

Adverse effects. Myelosuppression, mucositis, nausea and vomiting, hepatotoxicity, acute kidney injury (crystal nephropathy), neurotoxicity, pneumonitis, rash, and for pemetrexed fatigue, skin reactions and oedema.

Interactions. Reduced methotrexate clearance with NSAIDs, penicillins, proton pump inhibitors, probenecid and co-trimoxazole, with life-threatening pancytopenia.

Special groups.

• Pregnancy: avoid; teratogenic and abortifacient.
• Breastfeeding: avoid.
• Children: well tolerated at high doses with rescue.
• Older adults: reduce doses by creatinine clearance.
• Kidney impairment: avoid high-dose methotrexate; reduce intermediate and low doses; avoid pemetrexed under 45 mL/min.
• Liver impairment: avoid methotrexate in cirrhosis and active hepatitis.

Monitoring. Creatinine and methotrexate levels at 24, 48 and 72 hours, full blood count, liver enzymes, urine pH, and fluid balance.

Referral and escalation. A methotrexate level above 1 micromol/L at 48 hours, rising creatinine, or severe mucositis needs urgent specialist care and glucarpidase if available.