Novel Genetic Variants Explaining Severe Adverse Drug Events after Clinical Implementation of DPYD Genotype-Guided Therapy with Fluoropyrimidines: An Observational Study

被引:0
作者
Diaz-Villamarin, Xando [1 ]
Martinez-Perez, Maria [2 ]
Nieto-Sanchez, Maria Teresa [2 ]
Ruiz-Tueros, Gabriela [1 ]
Fernandez-Varon, Emilio [1 ,3 ]
Torres-Garcia, Alicia [1 ]
Astorga, Beatriz Gonzalez [1 ,4 ]
Blancas, Isabel [1 ,4 ]
Ianez, Antonio J. [5 ]
Cabeza-Barrera, Jose [1 ,2 ]
Moron, Rocio [1 ,2 ]
机构
[1] Inst Invest Biosanitaria Granada Ibs Granada, Granada 18012, Spain
[2] Hosp Univ San Cecilio, Hosp Pharm, Granada 18016, Spain
[3] Univ Granada, Ctr Biomed Res CIBM, Dept Pharmacol, Granada 18016, Spain
[4] Hosp Univ San Cecilio, Med Oncol, Granada 18016, Spain
[5] Hosp Reg Univ Malaga, Hosp Pharm, Malaga 29010, Spain
关键词
fluoropyrimidines; DPYD; personalized medicine; pharmacogenetics; clinical implementation; DIHYDROPYRIMIDINE DEHYDROGENASE; COLORECTAL-CANCER; CAPECITABINE; TOXICITY; SAFETY; PHARMACOGENETICS; POLYMORPHISMS; DEFICIENCY; EFFICACY; TUMORS;
D O I
10.3390/pharmaceutics16070956
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade >= 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35-23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41-28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.
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页数:18
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