Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing

Abstract

The fluoropyrimidines are the mainstay chemotherapeutic agents for the treatment of many types of cancers. Detoxifying metabolism of fluoropyrimidines requires dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene), and reduced or absent activity of this enzyme can result in severe, and sometimes fatal, toxicity. We summarize evidence from the published literature supporting this association and provide dosing recommendations for fluoropyrimidines based on DPYD genotype (updates at http://www.pharmgkb.org).

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

“…19 Clues that other DPYD genetic polymorphisms (DPYDrs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYDrs1801159, and DPYD-rs17376848) could have a role in the development of FL-related toxicities come from both DPWG guidelines 14 and looking at the most recent literature. 1,10 These polymorphisms have been previously observed in patients with low DPD enzymatic activity 20 and in some cases were associated to toxicity Grade 3 in the clinical setting. [21][22][23][24] The first aim of our study is to validate the specificity of three DPYD SNPs recommended by CPIC guidelines (i.e., DPYD-rs3918290, DPYD-rs55886062, and DPYD-rs67376798) in predicting the occurrence of severe toxicity events in a large set of oncological patients treated with FL in different clinical settings.…”

“…1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway.…”

“…15 Particularly, CPIC guidelines recommend choosing an alternative drug for patients who present two variant alleles (compound heterozygous or homozygous variant genotypes) and a 50% reduction of FL starting dose for patients with only one variant allele (heterozygous genotype) for any of these SNPs (http://www.pharmgkb.org/guideline/PA166122686). 1 Despite a number of studies and meta-analyses assessed the association between the DPYD genotyping test and the occurrence of severe toxicity related to FL, [8][9][10][11][16][17][18] its use is still scarcely widespread among clinicians possibly because the rarity of the considered DPYD SNPs renders the three DPYD-markers test sensitivity rather low. In addition, only scanty information is available about the cost-effectiveness of this analysis.…”

“…[21][22][23][24] The first aim of our study is to validate the specificity of three DPYD SNPs recommended by CPIC guidelines (i.e., DPYD-rs3918290, DPYD-rs55886062, and DPYD-rs67376798) in predicting the occurrence of severe toxicity events in a large set of oncological patients treated with FL in different clinical settings. 1 The second aim is to evaluate whether the additional testing of other investigational DPYD variants (DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYD-rs1801159, and DPYD-rs17376848) could increase the pharmacogenetic test sensitivity and is worthy to be integrated in the FL dosing guidelines.…”

Therapeutic drug monitoring of 5-fluorouracil

“…This is a single-nucleotide variant at the intron boundary of exon 14 that results in a splicing defect, skipping of the entire exon, and a completely inactive protein. The other DPD variants that are associated with reduced DPD enzyme activity and increased 5-FU toxicity include DPD *5, DPD *6, DPD *9A, DPD *13 (c.1679T>G; I560S; rs55886062), c.2846A>T (D949V; rs67376798), c.1236G>A (E412E; rs56038477) [76, 77]. …”