Page 134 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Rationale of
the therapeutic recommendation
Kinetic consequence
Clinical consequence
only applies if the variations are on different alleles. If both variations are on the same allele, the gene activity score assigned is between 1 and 1.5, depending on whether and how the two gene variations influence each other and on other factors that influence the DPD activity. Whether a gene activity score of 1 or 1.5 needs to be assigned in the case of two different genetic variations can only be determined by measuring the enzyme activity (phenotyping).
Treatment with tegafur in combination with the DPD inhibitor uracil in two patients with gene activity score 1 led to similar toxicity as found after treatment with 5-FU or capecitabine. However, four patients with an assigned gene activity score of 1 could be treated with 90% of the standard tegafur-uracil dose without grade 3-4 toxicity occurring. Similar to data found for 5-FU and capecitabine, treatment with a reduced dose of tegafur-uracil seems possible for patients who are assigned a gene activity score of 1. This is why a dose reduction or alternative is recommended.
Studies regarding the kinetic consequences are unavailable.
In a study, two patients had a comparable toxicity for treatment with tegafur/uracil as found for treatment with 5-FU or capecitabine. In another study, four patients could be treated with 90 % of the standard tegafur/uracil dose without grade 3-4 toxicity occurring. All six patients had the genotype *1/*2A.
Predicted phenotype: Gene activity score 1.5 Ref. 1,3
Therapeutic recommendation
Rationale of
the therapeutic recommendation
Kinetic consequence
Clinical consequence
Choose an alternative or start with a low dose and adjust the initial dose based on toxicity and efficacy.
Do not choose 5-FU or capecitabine, as these are also metabolised by DPD.
A substantiated recommendation for dose reduction cannot be made based on the literature. For 5-FU and capecitabine, starting with 75 % of the normal dose is recommended.
Treatment with tegafur in combination with the DPD inhibitor uracil in two patients with gene activity score 1.5 led to similar toxicity as found after treatment with 5-FU or capecitabine. However, four patients with the more deficient phenotype (gene activity score 1) could be treated with 90% of the standard tegafur-uracil dose without grade 3-4 toxicity occurring. Similar to data found for 5-fluorouracil and capecitabine, treatment with a reduced dose of tegafur-uracil seems possible for patients with gene activity score 1 or higher. This is why a dose reduction or alternative is recommended.
Studies regarding the kinetic consequences are unavailable.
Two patients with gene activity score 1.5 had a comparable toxicity for treatment with tegafur/uracil as found for treatment with 5-FU or capecitabine. Four patients with gene activity score 1 could be treated with 90 % of the standard tegafur/uracil dose without grade 3-4 toxicity occurring.
Abbreviations: Ref.: References; 5-FU: 5-fluorouracil; AUC: Area Under the Curve; DPD: dihydropyrimidine dehydrogenase; OR: Odds Ratio.
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