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.
Reference: PAGE 19 () Abstr 1730 [www.page-meeting.org/?abstract=1730]
Poster: Applications- Oncology