Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies
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...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/11/2837 |
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| author | Zachary L. Taylor Jesper Vang Elixabet Lopez-Lopez Natanja Oosterom Torben Mikkelsen Laura B. Ramsey |
| author_facet | Zachary L. Taylor Jesper Vang Elixabet Lopez-Lopez Natanja Oosterom Torben Mikkelsen Laura B. Ramsey |
| author_sort | Zachary L. Taylor |
| collection | DOAJ |
| description | 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: <i>SLCO1B1</i>. |
| first_indexed | 2024-03-10T10:38:59Z |
| format | Article |
| id | doaj.art-59db8fb3ce954fa282fbbdd105bd1658 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T10:38:59Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-59db8fb3ce954fa282fbbdd105bd16582023-11-21T23:04:54ZengMDPI AGCancers2072-66942021-06-011311283710.3390/cancers13112837Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric MalignanciesZachary L. Taylor0Jesper Vang1Elixabet Lopez-Lopez2Natanja Oosterom3Torben Mikkelsen4Laura B. Ramsey5Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH 45267, USADepartment of Health Technology, Technical University of Denmark, 2800 Lyngby, DenmarkDepartment of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country, UPV/EHU, 48940 Leioa, SpainPrincess Máxima Center for Pediatric Oncology, 3720 Utrecht, The NetherlandsDepartment of Pediatric Oncology, Aarhus University Hospital, 8200 Aarhus, DenmarkDivision of Research in Patient Services, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USAMethotrexate (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: <i>SLCO1B1</i>.https://www.mdpi.com/2072-6694/13/11/2837methotrexatepharmacokineticspharmacogeneticspediatricsacute lymphoblastic leukemiaosteosarcoma |
| spellingShingle | Zachary L. Taylor Jesper Vang Elixabet Lopez-Lopez Natanja Oosterom Torben Mikkelsen Laura B. Ramsey Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies Cancers methotrexate pharmacokinetics pharmacogenetics pediatrics acute lymphoblastic leukemia osteosarcoma |
| title | Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies |
| title_full | Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies |
| title_fullStr | Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies |
| title_full_unstemmed | Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies |
| title_short | Systematic Review of Pharmacogenetic Factors That Influence High-Dose Methotrexate Pharmacokinetics in Pediatric Malignancies |
| title_sort | systematic review of pharmacogenetic factors that influence high dose methotrexate pharmacokinetics in pediatric malignancies |
| topic | methotrexate pharmacokinetics pharmacogenetics pediatrics acute lymphoblastic leukemia osteosarcoma |
| url | https://www.mdpi.com/2072-6694/13/11/2837 |
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