Page 133 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Kinetic consequence
Clinical consequence
Studies regarding the kinetic consequences are unavailable.
Studies regarding the clinical consequences are unavailable. The SmPC states that
this combination is contraindicated in patients with DPD deficiency. This probably refers to gene activity score 0. No safe dose for 5-FU (the metabolite of tegafur) has been found for patients assigned a gene activity score of 0. In addition, four patients with a less deficient DPD activity (assigned a gene activity score of 1 or 1.5) had a comparable toxicity for treatment with tegafur/uracil as found for treatment with 5-FU or capecitabine.
Supplement
Predicted phenotype: Gene activity score 0.5 4 Ref. 1
Therapeutic recommendation
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 25% of the standard dose is recommended.
NOTE: This recommendation only applies if the two gene variations are on different alleles. If both variations are on the same allele, this patient is assigned a gene activity score of 1 and the recommendation for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
There are no data available on the use of tegafur in combination with a DPD inhibitor for gene activity score 0.5. The SPCs state that tegafur in combination with a DPD inhibitor is contraindicated in patients with a history of serious and unexpected reactions to fluoropyrimidine therapy, but do not substantiate this.
However, two patients using standard doses of tegafur-uracil who developed severe toxicity were found to be assigned partially deficient phenotypes of gene activity scores of 1 and 1.5. The toxicity was similar to that found in patients treated with capecitabine or 5-FU, both of which are given without a DPD inhibitor. The recommendation for 5-FU and capecitabine in patients with gene activity score 0.5 is to reduce the dose to 25% of the standard dose or to choose an alternative. This is why a dose reduction or alternative is also recommended for tegafur.
Studies regarding the kinetic consequences are unavailable.
Studies regarding the clinical consequences are unavailable. However, four patients with a less deficient DPD activity (assigned a gene activity score of 1 or 1.5) had a comparable toxicity for treatment with tegafur/uracil as found for treatment with 5-FU or capecitabine. In addition to this, four patients assigned a gene activity score of 1 could be treated with 90 % of the standard tegafur/uracil dose without grade 3-4 toxicity occurring.
Rationale of
the therapeutic recommendation
Kinetic consequence
Clinical consequence
Predicted phenotype: Gene activity score 1.0 Ref. 1-3
Therapeutic recommendation
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-FUand capecitabine, starting with 50 % of the standard dose is recommended.
NOTE: If a patient has two different gene variations that result in a partially functional DPD enzyme (e.g. c.2846A>T and c.1236G>A), this recommendation
table continues
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