Journal article
Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies
University of Cincinnati1
Department of Health Technology, Technical University of Denmark2
Bioinformatics, Department of Health Technology, Technical University of Denmark3
Cancer Systems Biology, Bioinformatics, Department of Health Technology, Technical University of Denmark4
Disease Data Intelligence, Bioinformatics, Department of Health Technology, Technical University of Denmark5
University of the Basque Country6
Princess Máxima Center for Pediatric Oncology7
Aarhus University Hospital8
Cincinnati Children's Hospital Medical Center9
High-dose methotrexate is commonly used to treat several types of cancer. While effective, elimination of high-dose methotrexate from the body is highly variable and delayed elimination can lead to serious and sometime life-threatening adverse events. There have been many clinical studies to better understand how genetics influence the variability in methotrexate elimination, mostly through candidate gene studies and three genome-wide association studies.
Unfortunately, there are conflicting results and some studies lack the appropriate replication and validation needed to confirm their effects on methotrexate elimination. Therefore, the purpose of this systematic review was to summarize all of the germline pharmacogenetic association studies of genetic associations influencing high-dose methotrexate elimination in children with cancer.
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.
Language: | English |
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Publisher: | MDPI |
Year: | 2021 |
Pages: | 2837 |
ISSN: | 20726694 |
Types: | Journal article |
DOI: | 10.3390/cancers13112837 |
ORCIDs: | 0000-0002-5309-3031 , 0000-0001-6417-3961 and Vang, Jesper |
Acute lymphoblastic leukemia Lymphoma Methotrexate Neoplasms. Tumors. Oncology. Including cancer and carcinogens Osteosarcoma Pediatrics Pharmacogenetics Pharmacokinetics RC254-282 acute lymphoblastic leukemia lymphoma methotrexate osteosarcoma pediatrics pharmacogenetics pharmacokinetics