Effect ofSLCO1B1Polymorphisms on High-Dose Methotrexate Clearance in Children and Young Adults With Leukemia and Lymphoblastic Lymphoma

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 inSLCO1B1(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/m(2)over 24 hours. We evaluated the contribution of clinical covariates andSLCO1B1genotype (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 theSLCO1B1variants individually further improved the model (P < 0.05 for each). An interaction between these variants was suggested when both were included (P = 0.017).SLCO1B1genotype should be considered in efforts to personalize HD MTX dosing.