Risk factors associated with high-dose methotrexate induced toxicities

ABSTRACT

Introduction

High-dose methotrexate (HDMTX) therapy poses challenges in various neoplasms due to individualized pharmacokinetics and associated adverse effects. Our purpose is to identify early risk factors associated with HDMTX-induced toxicities, paving the way for personalized treatment.

Areas covered

A systematic review of PubMed and Cochrane databases was conducted for articles from inception to July 2023. Eligible studies included reviews, clinical trials, and real-world analyses. Irrelevant studies were excluded, and manual searches and citation reviews were performed. Factors such as MTX exposure, drug interactions, demographics, serum albumin, urine pH, serum calcium, and genetic polymorphisms affecting MTX transport (e.g. SLCO1B1), intracellular folate metabolism (MTHFR), cell development (ARID5B), metabolic pathways (UGT1A1, PNPLA3), as well as epigenetics were identified.

Expert opinion

This comprehensive review aids researchers and clinicians in early identification of HDMTX toxicity risk factors. By understanding the multifaceted risk factors associated with hematologic malignancies, personalized treatment approaches can be tailored to optimize therapeutic outcomes.

KEYWORDS:

• Acute kidney injury
• hepatotoxicity
• high-dose methotrexate
• methotrexate exposure
• myelosuppression
• risk factor
• toxicity

Article highlights

• High-dose methotrexate therapy in various malignancies presents challenges due to individualized pharmacokinetics and adverse effects. The purpose of this review is to identify early risk factors associated with HDMTX-induced toxicities to optimize personalized treatment.

• Key risk factors for MTX toxicities include MTX exposure level, drug-drug interactions, demographics, serum albumin, urine pH, serum calcium, genetic polymorphisms, and epigenetics.

• Delayed MTX elimination complicates toxicity assessment due to challenges in adhering to strict sampling timeframes. Adjusting MTX dosage based on AUC proves more reliable for enhancing efficacy and minimizing adverse effects, especially when utilizing population pharmacokinetic modeling.

• Interactions between MTX and PPIs, ACEIs, ARBs, diuretics, and other chemotherapy drugs can affect renal clearance, potentially leading to increased methotrexate exposure and associated toxicities.

• Genetic polymorphisms can impact MTX transport (e.g. SLCO1B1), intracellular folate metabolism (MTHFR, cell development (ARID5B), and metabolic pathways (UGT1A1, PNPLA3).

• Specific miRNA polymorphisms (e.g. rs4149009 in SLCO1A2, rs3737966/rs35134728 in MTHFR, rs1051296 in SLC19A1) can potentially affect MTX levels, while miR-1208, miR-1206 and pre-miR-323b may be linked to hepatotoxicity and hematotoxicity. Additionally, DNA methylation in the GGH promoter may contribute to neurotoxicities.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by the National Key R&D Program of China (2020YFC2008306), Beijing Municipal Administration of Hospitals Incubating Program (PX2024020) and Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University (CCMU2023ZKYXY025).