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High-dose methotrexate (HD-MTX)–based regimens are the standard treatment for patients with primary central nervous system lymphoma (PCNSL); however, MTX has extensive interpatient variability in pharmacokinetics and clinical outcomes, with genetic variation an important factor involved in the variability in drug response. 123 PCNSL patients who received 524 courses of chemotherapy were genotyped for 42 single nucleotide polymorphisms in MTX pathway. The relationship between these polymorphisms and the pharmacokinetics, clinical outcomes, and toxicity of MTX was explored using both univariate and multivariate analyses. We found  ABCB1  rs2032582 and  GGH  rs2305558 were substantially associated with the pharmacokinetics of MTX. Patients with  GGH  rs2305558 T and  ABCB1  rs2032582 non-G allele had a higher C max  increased by 20.5%, area under the concentration-time curve (AUC 0-48h ) increased by 19.6% and lower clearance decreased by 19.6%.  ABCB1  rs1045642 and rs2032582 might be independent predictors of progression-free survival. Patients with  ABCB1  rs1045642 non-A and rs2032582 G allele correlated with higher progression risk of the disease. Furthermore,  ATIC  rs3821353 was associated with MTX-induced hepatotoxicity (Grade ≥ 2). These variants may serve as biomarkers to predict the pharmacokinetics, clinical outcomes, and hepatotoxicity of MTX and contribute to personalized therapy for PCNSL patients.

expert review of clinical pharmacology

Germline genetic variations in methotrexate pathway are associated with pharmacokinetics, outcome, and toxicity in patients with primary central nervous system lymphoma