Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies

Abstract

Methotrexate (MTX) is a mainstay therapeutic agent administered at high doses for the treatment of pediatric and adult malignancies, such as acute lymphoblastic leukemia, osteosarcoma, and lymphoma. Despite the vast evidence for clinical efficacy, high-dose MTX displays significant inter-individual pharmacokinetic variability. Delayed MTX clearance can lead to prolonged, elevated exposure, causing increased risks for nephrotoxicity, mucositis, seizures, and neutropenia. Numerous pharmacogenetic studies have investigated the effects of several genes and polymorphisms on MTX clearance in an attempt to better understand the pharmacokinetic variability and improve patient outcomes. To date, several genes and polymorphisms that affect MTX clearance have been identified. However, evidence for select genes have conflicting results or lack the necessary replication and validation needed to confirm their effects on MTX clearance. Therefore, we performed a systematic review to identify and then summarize the pharmacogenetic factors that influence high-dose MTX pharmacokinetics in pediatric malignancies. Using the PRISMA guidelines, we analyzed 58 articles and 24 different genes that were associated with transporter pharmacology or the folate transport pathway. We conclude that there is only one gene that reliably demonstrates an effect on MTX pharmacokinetics: SLCO1B1.

The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis

“…This is the primary circulating form of folate, which is needed to reduce the toxic homocysteine to methionine. Through this process, folate is an important donor of methyl groups for all intracellular methylation processes (Taylor et al, 2021). The mutation 677C>T (rs1801133) causes a change of alanine to valine in the protein, and the mutation 1298A>C (rs1801131) causes the replacement of glutamate by valine, resulting in decreased enzyme activity of MTHFR (Robien and Ulrich, 2003).…”

“…First, the outcome measures we investigated were clinical outcomes of HDMTX-related toxicities or prognosis and not the plasma concentration or other pharmacokinetic outcomes of MTX, since the relationships of clinical outcomes and plasma concentration still remain to be verified. And notably, a recent systematic review has discussed on pharmacogenetic factors influencing HDMTX pharmacokinetics (Taylor et al, 2021). Second, data of prognosis outcomes was substantially lacking, which made the quantitative analysis unfortunately impossible for the most prognosis outcomes.…”

Protection of Hesperidin against Methotrexate- Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

“…For more than six decades, methotrexate (MTX) has been successfully used in a high dose for the treatment of various types of cancers 1 and in a relatively smaller dose to control autoimmune diseases. 2 Unfortunately, MTX, especially at high dosages, might cause severe acute renal toxicity in up to 12 % of patients.…”

Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: A review

“…Наиболее изучен полиморфизм rs1805087 (с.2756A>G). В большинстве исследований не удалось установить связь между этим полиморфизмом и кинетикой MTX [23][24][25]37].…”