Cyclophosphamide, Methotrexate, and 5-Fluorouracil Population Pharmacokinetic Models with Pharmacogenetic Covariates
P. Kellie Turner(1,3), Johanne Bray(1), David Jamieson(1), Aurélie Petain(2), Antonin Schmitt(2), Michael Cole(1), Etienne Chatelut(2), Alan V. Boddy(1)
(1) Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; (2) (2) Institut Claudius Regaud, Toulouse, France; (3) (3) Eli Lilly and Company Limited, Windlesham, Surrey, UK
Objectives: The purpose of this study was to evaluate the effect of single nucleotide polymorphisms (SNPs) in genes involved in the pharmacokinetics of cyclophosphamide, methotrexate, and 5-fluorouracil in women with breast cancer using a population pharmacokinetics approach. We examined candidate SNPs in cytochrome P450 (CYP) 2B6 (CYP2B6); CYP3A4/5; CYP2C19; nuclear receptor subfamily 1, group I, member 2 (NR1I2/PXR); NR1I3/CAR; solute carrier family 19 (folate transporter), member 1 (SLC19A1/RFC); ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2/BCRP); NAD(P)H dehydrogenase, quinone 2 (NQO2); and dihydropyrimidine dehydrogenase (DPYD).
Methods: DNA was extracted from formalin fixed paraffin-embedded biopsy tissue from 43 women, and genotyping was done by TaqMan SNP genotyping allelic discrimination and restriction fragment length polymorphism (RFLP) analysis. The following SNPs were evaluated: CYP2B6*5, CYP2B6*13, CYP2B6*4, CYP2C19*2A, CYP2C9*2, CYP2C9*3, CYP3A5*3, CAR 540C>T, PXR-131G>T, PXR -1135C>T, NQO2 F47L, ABCG2 421C>A, RFC 696A>G, RFC 1293+707G>T, DPYD*5, DPYD*9A, DPYD*2A. SNP genotypes were evaluated as covariates in population pharmacokinetic models using NONMEM software.
Results: Cyclophosphamide clearance was 28% lower in CYP2B6*5 heterozygotes and 14% lower in CYP2C19*2 heterozygotes compared to wild-type individuals. However, these SNPs were not significant covariates in the final model. The NQO2F47L polymorphism was a significant covariate for cyclophosphamide clearance [23% (95% confidence interval 10-36%) lower in heterozygotes compared to wild-type]. 5-FU clearance was 20% lower (95% confidence interval 3-39%) in DPYD*2A heterozygotes compared to wild-type.
Conclusions: Of the 17 SNPs evaluated in this study, only those in NQO2 and DPYD were significant covariates in the models for cyclophosphamide and 5-FU pharmacokinetics.
This study was funded by Cancer Research UK in partnership with the Department of Health (UK) and Institut National du Cancer (France) as an Experimental Cancer Medicine Fellowship Grant.