How to dose Leucovorin (folinic acid) in patients with impaired renal function (low eGFR)?

From the Guidelines

Leucovorin does not require dose adjustment in patients with impaired renal function, as it is primarily metabolized in the liver with minimal renal excretion, allowing for standard dosing to be maintained regardless of the patient's estimated glomerular filtration rate (eGFR) or creatinine clearance. When considering the dosing of leucovorin in patients with low eGFR, it's essential to understand that the medication's pharmacokinetics are not significantly altered by renal impairment. The dosing of leucovorin can vary based on the specific regimen and indication, as outlined in guidelines such as those from the NCCN 1, which provide detailed recommendations for various chemotherapy regimens that include leucovorin. Some key regimens include:

• FOLFOXIRI, which involves leucovorin 400 mg/m² on day 1, among other medications 1
• Bolus or infusional 5-FU/leucovorin regimens, with leucovorin doses ranging from 200 mg/m² to 500 mg/m² 1
• Biweekly and weekly regimens with varying leucovorin doses 1. Given that leucovorin's metabolism and excretion are not heavily dependent on renal function, the standard dosing can be used without adjustment for patients with impaired renal function, simplifying its administration in clinical practice.

From the FDA Drug Label

DOSAGE AND ADMINISTRATION ... In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Serum creatinine and methotrexate levels should be determined at 24-hour intervals If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 x 10 -6 M or the 48 hour level is greater than 9 x 10 -7 M, the dose of leucovorin should be increased to 150 mg (100 mg/m2) IV every 3 hours until the methotrexate level is less than 10 -8 M. Patients who experience delayed early methotrexate elimination are likely to develop reversible non-oliguric renal failure In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0. 05 micromolar and the renal failure has resolved.

The dosing of Leucovorin in patients with impaired renal function (low eGFR) should be guided by monitoring of serum methotrexate levels and serum creatinine levels. If there is a significant increase in serum creatinine or methotrexate levels, the dose of Leucovorin should be increased to 150 mg (100 mg/m2) IV every 3 hours. Additionally, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status 2.

• Key considerations:
  • Monitor serum methotrexate and creatinine levels
  • Increase Leucovorin dose if necessary
  • Provide hydration and urinary alkalinization
  • Close monitoring of fluid and electrolyte status 2

From the Research

Dosing Leucovorin in Patients with Impaired Renal Function

• The dosing of Leucovorin (folinic acid) in patients with impaired renal function (low eGFR) is crucial to avoid toxicity and ensure efficacy 3.
• However, there is limited direct evidence on the optimal dosing of Leucovorin in patients with low eGFR.
• A study on the comparison of two doses of Leucovorin in severe low-dose methotrexate toxicity found that there was no significant difference in survival or time-to hematological recovery between the two doses of Leucovorin 4.
• Another study on the pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil, and Leucovorin given on a weekly schedule found that Leucovorin decreased 5-FU plasma clearance and prolonged the half-life 5.
• A study on high-dose Leucovorin as sole therapy for methotrexate toxicity found that high-dose Leucovorin can be used as a sole therapy for methotrexate toxicity without the need for extracorporeal removal and with tolerable morbidity 6.
• A phase I study of gemcitabine, 5-fluorouracil, and Leucovorin in patients with advanced, recurrent, and/or metastatic solid tumors found that the combination of gemcitabine, Leucovorin, and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile 7.

Considerations for Dosing Leucovorin in Low eGFR

• Patients with severe renal impairment (eGFR < 30 ml/min/1.73 m2) may require dose adjustments to avoid toxicity 3.
• The dosing of Leucovorin should be individualized based on the patient's renal function, as well as other factors such as the specific chemotherapy regimen and the patient's overall health status.
• Further studies are needed to determine the optimal dosing of Leucovorin in patients with impaired renal function.

Key Findings

• Limited direct evidence on the optimal dosing of Leucovorin in patients with low eGFR 3, 4, 5, 6, 7.
• High-dose Leucovorin can be used as a sole therapy for methotrexate toxicity without the need for extracorporeal removal and with tolerable morbidity 6.
• The combination of gemcitabine, Leucovorin, and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile 7.