High-Dose Methotrexate Pharmacotherapy in Pediatric Oncology
Summary
High-dose methotrexate (HD-MTX) remains a cornerstone of treatment for a range of paediatric malignancies, notably acute lymphoblastic leukaemia and osteosarcoma. Administered intravenously at doses significantly above conventional levels, HD-MTX exerts its antineoplastic effect through inhibition of dihydrofolate reductase, thereby interrupting folate metabolism and DNA synthesis in rapidly dividing cells. The regimen’s efficacy is tempered by a narrow therapeutic window and considerable inter-patient variability in drug clearance, driven by differences in renal function, transporter activity and genetic polymorphisms. To mitigate toxicity, particularly mucositis, nephrotoxicity and myelosuppression, clinicians employ intensive hydration, urine alkalinisation and leucovorin rescue. Leucovorin, a reduced folate analogue, competitively replenishes intracellular folate pools once plasma MTX levels have declined to safe thresholds. Ongoing efforts in model-informed precision dosing, pharmacogenetic profiling and real-time monitoring aim to individualise HD-MTX administration. These strategies include adjustment of dosing based on prior clearance, genotype-guided dose selection for transporters such as SLCO1B1 and the use of predictive tools to identify patients at risk of delayed elimination. The overarching goal is to optimise antitumour efficacy while minimising adverse events and facilitating timely progression through multi-agent chemotherapy protocols.
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High-Dose Methotrexate Pharmacotherapy in Pediatric Oncology publication trend
The graph below shows the total number of articles in high-dose methotrexate pharmacotherapy in pediatric oncology across all publications each year (not limited to Nature Index journals).
Technical terms
Therapeutic window: The plasma concentration range in which a drug is efficacious without causing unacceptable toxicity.
Pharmacokinetics: The study of drug absorption, distribution, metabolism and excretion over time.
Leucovorin rescue: Administration of reduced folate to protect normal cells from methotrexate toxicity once drug levels have fallen below a safety threshold.
SLCO1B1: A gene encoding an organic anion transporter critical for hepatic uptake and clearance of methotrexate.
Population pharmacokinetic (PopPK) model: A mathematical model describing how a drug’s concentration–time profile varies across a patient population, accounting for covariates such as age and renal function.
References
- External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia. Pharmaceutics (2023).
- Predicting delayed methotrexate elimination in pediatric acute lymphoblastic leukemia patients: an innovative web-based machine learning tool developed through a multicenter, retrospective analysis. BMC Medical Informatics and Decision Making (2023).
- Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies. Cancers (2021).
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