Effect of SLCO1B1 Polymorphisms on High‐Dose Methotrexate Clearance in Children and Young Adults With Leukemia and Lymphoblastic Lymphoma

• Published in: Clinical and translational science Vol. 14; no. 1; pp. 343 - 353
• Main Authors: Schulte, Rachael R., Choi, Leena, Utreja, Nipun, Van Driest, Sara L., Stein, C. Michael, Ho, Richard H.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2021; John Wiley and Sons Inc; Wiley
• Subjects: Adolescent; Adult; Age; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacokinetics; Biobanks; Blood cancer; Body Weight; Cancer therapies; Child; Child, Preschool; Children; Data collection; Deoxyribonucleic acid; DNA; Dosage; Dose-Response Relationship, Drug; Drug dosages; Ethnicity; Female; Human subjects; Humans; Infant; Leukemia; Leukemia, Lymphoid - blood; Leukemia, Lymphoid - drug therapy; Liver-Specific Organic Anion Transporter 1 - genetics; Lymphoma; Male; Methotrexate; Methotrexate - administration & dosage; Methotrexate - pharmacokinetics; Models, Biological; Patients; Pharmacogenomic Testing - statistics & numerical data; Pharmacogenomic Variants; Pharmacokinetics; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - blood; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Therapeutic drug monitoring; Young Adult; Young adults
• ISSN: 1752-8054; 1752-8062; 1752-8062
• DOI: 10.1111/cts.12879

High‐dose (HD) methotrexate (MTX) is a critical component of treatment for hematologic malignancies in children and young adults. Therapeutic drug monitoring is necessary due to substantial interindividual variation in MTX clearance. Common function‐altering polymorphisms in SLCO1B1 (encodes OATP1B1, which transports MTX) may contribute to clearance variability. We performed pharmacokinetic modeling using data for 106 children and young adults treated with HD MTX for hematologic malignancies; of 396 total courses of HD MTX, 360 consisted of 5 g/m2 over 24 hours. We evaluated the contribution of clinical covariates and SLCO1B1 genotype (388A>G and 521T>C) to MTX clearance variability. Of the clinical covariates studied, patient weight improved the pharmacokinetic model most significantly (P < 0.001). The addition of the SLCO1B1 variants individually further improved the model (P < 0.05 for each). An interaction between these variants was suggested when both were included (P = 0.017). SLCO1B1 genotype should be considered in efforts to personalize HD MTX dosing.