Reduced Folate Carrier Single Nucleotide Polymorphism Associated with Methotrexate Clearance in Breast Cancer Patients
P.K. Turner (1), M. Cole (1), A. Petain (2), M.A. Batey (1), S.L. Beare (1), É. Chatelut (2), A.V. Boddy (1)
P.K. Turner (1), M. Cole (1), A. Petain (2), M.A. Batey (1), S.L. Beare (1), É. Chatelut (2), A.V. Boddy (1)
Objective: Previously we have developed a population pharmacokinetic (PK) model for methotrexate (MTX) in breast cancer patients [1]. This model included covariates such as renal function (i.e., glomerular filtration rate, GFR) and body size. Reduced folate carrier (RFC) is a ubiquitously expressed transmembrane protein that transports both folates and MTX into cells. SNP's in genes involved in MTX PK such as reduced folate carrier (RFC) may also be significant covariates in population PK models. The aim of the present study was to identify SNP's that explain interindividual variation in MTX PK.
Methods: DNA was isolated from tumour blocks. SNP's in drug metabolizing enzymes important in MTX PK were genotyped using TaqMan genotyping assays. We used nonlinear mixed effects modelling software (NONMEM version VI) to refine the previously published MTX population PK model. A two-compartment model was fit to the MTX plasma concentration-time data. We investigated the influence of patient covariates (e.g., RFC genotype and GFR) on MTX PK parameters.
Results: The patient population consisted of 35 breast cancer patients. We identified a SNP (rs12659) in RFC with novel functional significance. The genotype frequencies were in Hardy-Weinberg equilibrium. Mean MTX clearance in patients homozygous for the G allele was significantly lower than in carriers of the A allele (126 vs. 152 mL/min, p= 0.04, Mann-Whitney U Test). The population PK model for MTX clearance was significantly improved by including RFC genotype as a covariate instead of GFR. Including both RFC genotype and GFR as covariates did not significantly improve the model over genotype alone.
Conclusion: We have demonstrated that RFC genotype is a more significant covariate in MTX clearance than GFR. These results may contribute to therapeutic individualization and optimization in a variety of cancers with an aim towards improving survival and reducing toxicity. This work is supported by Department of Health, Institut National du Cancer, and Cancer Research UK.
Reference:
[1] Batey MA, Wright JG, Azzabi A, Newell DR, Lind MJ, Calvert AH, Boddy AV. Population pharmacokinetics of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Eur J Cancer 2002, 38, 1081-1089.