Page 63 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

DPWG guideline for DPYD and fluoropyrimidines
Over 160 different allele variants in DPYD have been identified and described in literature.13 According to the gnomAD browser,14 which contains whole exome data of almost 140,000 individuals, DPYD contains 2,190 known variants. The prevalence of individual variants is low. The effect of genetic variation on DPD enzyme activity is not fully established for the majority of variants and the size of the effect can differ between variants.
The frequency of the various DPYD variants and the associated phenotypes appears
to vary significantly between nations and ethnic groups. For example, in the Caucasian 4 population, approximately 3─5% has a partial DPD enzyme deficiency and 0.1─0.2% has
a complete DPD enzyme deficiency. On the other hand, approximately 8% of the African American population has a partial DPD enzyme deficiency.15,16
Gene-drug interaction
Pharmacological mechanism
A schematic overview of fluoropyrimidine metabolism is shown in Figure 1. The DPD enzyme is mainly found in liver, but also intestinal mucosa, leucocytes, tumour cells and other tissues. Over 80% of 5-FU is inactivated to 5-fluoro-5,6-dihydrouracil (DHFU) by DPD. The decreased metabolic activity of DPD leads to increased intracellular concentrations of active metabolites of 5-FU.17 The increased intracellular concentration of 5-fluoro-2’-deoxyuridine- 5’-monophosphate (FdUMP) increases the risk of toxicity such as diarrhoea, hand-foot syndrome, mucositis and myelosuppression. Variants in the DPYD gene can result in reduced or even absent DPD enzyme activity, increasing the risk of severe toxicity. For example, 73% of the patients with DPYD*2A experienced severe toxicity when treated with a full dose, compared to 23% of *1 allele carriers (wild-type patients) who experienced toxicity.18 Many enzymes are involved in fluoropyrimidine metabolism, however, this guideline is limited to the role of the DPD enzyme in causing toxicity.
Since the genetic variation in DPYD only partially determines DPD enzyme activity, these guidelines for dose adjustment based on the predicted phenotype are no more than a tool that can be used to achieve the desired intracellular concentration of the active metabolite, to minimize risk of toxicity. The absence of tested variants does not eliminate the risk of toxicity. Pharmacokinetic dose adjustment (guided by steady-state plasma concentrations or AUC) may also be useful to optimize the dose of 5-FU. This is, however, currently not routinely used for capecitabine and tegafur, as they are mainly converted into 5-FU within tissue.
DPYD variants associated with toxicity
The variants known or suspected to have an effect on DPD enzyme activity, are listed in Table 1. These variants are mapped by the level of evidence for which association with toxicity has been established (columns) and the variant’s effect on DPD enzyme activity (rows). Novel variants in DPYD will continue to be identified with the introduction of next generation sequencing techniques to clinical practice. However, in order for these variants to be included in Table 1, sufficient evidence regarding the effect on enzyme function or the onset of toxicity must be investigated, possibly by using the DPYD-Varifier19 or by phenotyping patients who carry a novel variant. An update of this guideline will be published when a
61