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

Abstract

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/m 2 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. Methotrexate (MTX) is an antifolate chemotherapy agent. High-dose (HD) MTX regimens (> 500 mg/m 2 per dose), integral to the treatment of children and young adults with acute lymphoblastic leukemia (ALL) and other malignancies, are administered intravenously and require significant inpatient supportive care to reduce risk for toxicities. The addition of HD MTX to therapy for high-risk B-cell ALL significantly improved survival for high-risk B-cell ALL 1 and reduced central nervous system relapse in lymphoblastic lymphoma. 2,3 Although highly effective, HD MTX has a narrow therapeutic window with potentially severe toxicities (e.g., myelosuppression, mucositis, hepatotoxicity, nephrotoxicity, and neurotoxicity). 4 Drug level monitoring is required to reduce risk for toxicities. Greater than 90% of children diagnosed with cancer in the United States are treated per Children's Oncology Group (COG) protocols, on which supportive care measures are adjusted for supratherapeutic MTX levels but no changes are made for low MTX levels, suggesting rapid clearance. 4 Drug clearance following HD

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

“…The SNP most often tested for association with MTX PK measures is rs4149056, which encodes a T521C transition that reduces the localization of the transporter to the surface of the cell and causes a severe reduction in transport of MTX in vitro [ 64 ]. This variant was universally associated with decreased MTX clearance among all the studies included in this review [ 21 , 22 , 27 , 28 , 32 , 33 , 34 , 35 , 38 , 43 , 49 , 50 , 51 , 52 , 54 , 55 ]. The rs4149056 common variant is included in two * alleles, the no function *5 (no other coding variants) allele and the more common *15 (with rs2306283 A > G) allele.…”

“…The rs2306283 A > G variant is included in many * alleles, and is associated with increased transporter expression. Most studies found that this SNP associated with faster MTX clearance [ 33 , 54 ], but one found that it associated with slower clearance [ 27 ].…”

“…The following information is summarized and presented in Table 1. [33], [38], [54] [22,27], [28], [32], [33], [34], [35], [38,43], [49], [50], [51], [52], [54], […”

Population Pharmacokinetics of High-Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia

“…It is metabolized to 7-hydroxy-MTX in the liver, which contributes to MTX activity (Csordas et al, 2013), and a small part of MTX is excreted in the bile with partial intestinal reabsorption. Several efflux and uptake transporters (e.g., BCRP, MRP2, MRP3, MRP4, OAT1, and OAT3) are involved in the pharmacokinetic (PK) disposition process of MTX, which could lead to substantial variability in PK exposure (Treviño et al, 2009;Leveque et al, 2011;Ramsey et al, 2013;Schulte et al, 2021). Recent studies suggested that MTX elimination varied significantly between HD-MTX courses, and extremely delayed MTX elimination was observed in approximately 0.5% of pediatric patients with ALL (Svahn et al, 2017).…”

A review of pharmacogenetic aspects of methotrexate and 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia treatment

“…Множество транспортеров и ферментов участвуют в метаболизме фолиевой кислоты, а другие обеспечивают всасывание и транспорт МТХ, что влияет на ФК МТХ. Активность белков-транспортеров оказы-вает влияние на концентрации препаратов в плазме крови и тканях, тем самым определяя лекарственную токсичность [5,9,10]. Выявление наличия полиморфизмов генов, кодирующих белки-переносчики МТХ и ферменты его биотрансформации, позволяет прогнозировать риск МТХ-индуцированной токсичности со стороны кожи и слизистых, печени, почек, нервной системы [2,6].…”