Related Experiment Videos
Raised plasma methotrexate concentrations following intrathecal administration in children with renal dysfunction
R E Gregory1, C H Pui, W R Crom
1Clinical Pharmacokinetics and Pharmacodynamics Section, St. Jude Children's Research Hospital, Memphis, TN 38105.
Abstract:
Plasma methotrexate (MTX) concentrations were measured following intrathecal (IT) MTX treatment in four patients with acute lymphocytic leukemia and acute renal dysfunction. All four patients had raised serum MTX concentrations to potentially cytotoxic concentrations for a prolonged period of time, (96-120 h). In contrast, serum MTX concentrations after the same dosage of IT treatment ranged from undetectable to 0.11 microM by 15-24 h in seven control patients with normal renal function, and were undetectable by 48 h in all controls. The terminal MTX T1/2 was 19-44 h in the patients with renal dysfunction. Decreased renal clearance or a rapid efflux of MTX from cerebrospinal fluid, or both, could account for the high and sustained concentrations. Plasma MTX concentrations after IT treatment were normal in two patients treated after their renal function returned to normal. Patients with renal dysfunction should be carefully monitored for plasma MTX concentrations and may require leucovorin to prevent systemic side-effects after IT MTX treatment.
Insights
Patients with acute lymphocytic leukemia and renal dysfunction receiving intrathecal methotrexate (IT MTX) experienced prolonged, potentially toxic MTX levels. Careful monitoring and leucovorin may be needed to prevent systemic side effects.
Area of Science:
- Oncology
- Pharmacokinetics
- Nephrology
Background:
- Intrathecal methotrexate (IT MTX) is a critical treatment for acute lymphocytic leukemia (ALL).
- Renal dysfunction can significantly alter drug pharmacokinetics, potentially leading to toxicity.
Observation:
- Four patients with ALL and acute renal dysfunction exhibited elevated plasma methotrexate (MTX) concentrations for 96-120 hours after IT MTX.
- In contrast, control patients with normal renal function cleared MTX to undetectable levels within 48 hours.
- The terminal MTX half-life (T1/2) was prolonged (19-44 hours) in patients with renal dysfunction.
Findings:
- Patients with renal dysfunction experienced prolonged, potentially cytotoxic systemic MTX exposure following IT administration.
- Reduced renal clearance or rapid cerebrospinal fluid efflux of MTX likely contributed to sustained high plasma concentrations.
- MTX levels normalized in patients after renal function recovery.
Implications:
- Close monitoring of plasma MTX concentrations is essential in ALL patients with renal dysfunction receiving IT MTX.
- Prophylactic leucovorin administration may be necessary to mitigate systemic MTX toxicity in this vulnerable population.
- These findings underscore the importance of assessing renal function in IT MTX therapy management.