Page 69 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

DPWG guideline for DPYD and fluoropyrimidines
scores. However, the increased risk of toxicity for patients assigned gene activity scores 0 and 0.5 can be concluded based on the confirmed association for gene activity scores 1 and 1.5, where deficiency is less, and is further supported by cases of patients assigned gene activity scores 0 and 0.5 who developed severe toxicity. Only one study investigating clinical outcome concluded there was no effect of variants on risk of toxicity. Based on the systematic review, the DPWG concludes that a gene-drug interaction is present and that DPD enzyme deficiency increases risk of severe toxicity in patients using capecitabine/5-FU. The highest quality of evidence concluding a gene-drug interaction was scored 4.
In the systematic review performed for tegafur with the DPD inhibitor uracil, one case report described four patients who used standard doses and developed severe toxicity. These patients were assigned DPYD-gene activity scores 1 and 1.5. Toxicity (CTC-AE grade 4) was similar to that reported in patients treated with 5-FU or capecitabine, both of which are given without a DPD inhibitor. There were no data available for patients assigned DPYD- gene activity score 0 or 0.5, however the increased risk of toxicity among these patients can be concluded based on the confirmed association with toxicity for gene activity scores 1 and 1.5, where deficiency is less. Based on the systematic review, the DPWG concludes that there is a clinically relevant gene-drug interaction present and that DPD enzyme deficiency increases risk of severe toxicity in patients using tegafur with DPD inhibitors. The highest quality of evidence concluding a gene-drug interaction was scored 2.
Pharmacotherapeutic recommendations
The DPWG therapeutic recommendation using a patient’s pre-therapeutic PGx test result to optimize starting dose of 5-FU/capecitabine and tegafur with DPD inhibitors is summarized in Supplementary Table 5 and 6, respectively.
In brief, when initiating 5-FU, capecitabine or tegafur pharmacotherapy, a gene activity score of 0 recommends choosing an alternative chemotherapy or determining the residual DPD enzyme activity and adjusting the fluoropyrimidine starting dose accordingly. When initiating 5-FU or capecitabine, a gene activity score of 0.5, 1 or 1.5 recommends a starting dose of 25%, 50% or 75%, respectively. Further titration of the dose is possible, guided by toxicity. When initiating tegafur, a gene activity score of 0.5, 1 or 1.5 recommends choosing an alternative chemotherapy or starting with a lower dose and titrating dose based upon toxicity. A gene activity score of 2 (reference value) does not result in a recommendation for dose adaptation for 5-FU, capecitabine or tegafur. If genotype results cannot predict the gene activity score correctly, for example due to multiple identified variants, it is advised to determine the DPD enzyme activity to define an initial starting dose.
Where possible, dose adjustments have been calculated based on 5-FU clearance or AUC after administration of 5-FU or capecitabine. Data were also extrapolated to tegafur with DPD inhibitor, as this compound also follows the same catabolic and anabolic routes after conversion to 5-FU after clearance of the DPD inhibitor from the body. Data on 5-FU clearance are only available for patients carrying DPYD*1/DPYD*2A, DPYD*1/c.2846A>T and DPYD*2A/c.2846A>T. There are data from one patient with DPYD*1/DPYD*13 who developed severe toxicity after 5-FU use, from one patient with c.2846A>T/c.2846A>T and from one patient with c.1236G>A/c.2846A>T.
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