How do leucovorin rescue and urine alkalinization affect methotrexate levels in chemotherapy?

Methotrexate Levels with Leucovorin Rescue and Urine Alkalinization in Chemotherapy

Both leucovorin rescue and urine alkalinization are essential strategies for reducing methotrexate levels and preventing toxicity during high-dose methotrexate chemotherapy regimens. 1, 2

Leucovorin Rescue Effect on Methotrexate Levels

• Leucovorin (folinic acid) rescue is mandatory when administering high-dose methotrexate (3-8 g/m²) to prevent life-threatening toxicity by providing reduced folates that bypass methotrexate's inhibition of dihydrofolate reductase 1
• Leucovorin dosing is typically 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses starting 24 hours after beginning methotrexate infusion 2
• For delayed methotrexate elimination or evidence of renal injury, leucovorin dosing must be increased to 150 mg IV every 3 hours until methotrexate levels fall below 1 micromolar 2, 3
• Leucovorin rescue should be continued until methotrexate levels fall below 0.05 micromolar to prevent toxicity 2

Urine Alkalinization Effect on Methotrexate Levels

• Urinary alkalinization (maintaining urine pH ≥7.0) significantly increases methotrexate solubility and prevents precipitation of methotrexate in renal tubules 1, 4
• Low urine pH is significantly associated with high-risk methotrexate concentrations (≥1.0 micromolar at 42 hours) 5
• Alkalinization with sodium bicarbonate has been shown to decrease the incidence of acute nephrotoxicity and subsequent myelotoxicity in patients receiving high-dose methotrexate 6
• Inadequate alkalinization is a major risk factor for delayed methotrexate clearance and subsequent toxicity 5

Combined Approach for Methotrexate Management

• High-dose methotrexate administration requires a combination of:

  • Intense hydration (maintaining high urine output)
  • Urinary alkalinization (pH >7.0)
  • Leucovorin rescue
  • Close monitoring of methotrexate levels and renal function 1

• A more aggressive hydration and alkalinization regimen can reduce the frequency of high-risk methotrexate concentrations from 22% to 7% of courses, and the frequency of toxicity from 26% to 11% 5

Monitoring and Adjusting Therapy

• Serum creatinine and methotrexate levels should be determined at least once daily during high-dose methotrexate therapy 2
• If methotrexate levels remain high despite standard measures, treatment with carboxypeptidase G2 should be considered 1
• For patients with prolonged high levels of methotrexate who require additional cycles, methylene-tetrahydrofolate reductase (MTHFR) genotyping is recommended to identify individuals at increased risk of toxicity 1

Common Pitfalls and Caveats

• High-dose methotrexate causes a subclinical decrease in glomerular filtration rate with each administration, even in non-toxic courses 4

• Monitoring of 24-hour serum creatinine and methotrexate levels can predict patients at risk for serious toxicity 6

• Prompt increase in leucovorin dose (within 24-36 hours) can prevent myelosuppression in patients with delayed methotrexate clearance 6

• Factors associated with high-risk methotrexate concentrations include:

  • Higher methotrexate AUC
  • Low urine pH
  • Emesis
  • Low methotrexate clearance
  • Low urine output relative to intake
  • Use of antiemetics during methotrexate infusion
  • Concurrent intrathecal therapy 5

• Administering high-dose methotrexate without monitoring plasma levels is dangerous, particularly in elderly patients 7