Page 132 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Supplementary Table 6. Dutch Pharmacogenetics Working Group (DPWG) Guideline for DPYD and tegafur with DPD inhibitors: the therapeutic recommendation and its rationale, and the kinetic and clinical consequences for each aberrant gene activity score
Predicted phenotype: Gene activity score 0 Ref. 1
Therapeutic recommendation
Choose an alternative.
Do not choose 5-FU or capecitabine, as these are also metabolised by DPD.
If an alternative is not possible: start with a very low dose and adjust the initial dose based on toxicity and efficacy.
A substantiated recommendation for dose reduction cannot be made based on the literature. The recommendation for 5-FU and capecitabine is to determine the residual DPD activity in mononuclear cells from peripheral blood and to adjust the initial dose accordingly. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the standard capecitabine dose (150 mg every 5 days). A patient with undetectable DPD activity tolerated 0.43% of the standard capecitabine dose (150 mg every five days with every third dose skipped)
The average Caucasian DPD activity is 9.9 nmol/hour per mg protein.
NOTE: If a patient carries two different gene variations that lead to a non-functional DPD enzyme (e.g. *2A and *13), this recommendation only applies if the 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 patients assigned a gene activity score of 0. The SPCs state that tegafur in combination with a DPD inhibitor is contraindicated in patients with dihydropyrimidine dehydrogenase deficiency, 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 (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 DPD inhibitor is 200 times more potent in the tegafur-gimeracil-oteracil combination. However, 5-FU is still metabolised by DPD after administration of this combination and DPD is therefore also involved in 5-FU clearance.
For 5-FU and capecitabine, the maximally tolerated dose of 50% of the normal dose for *1/*2A indicates that the maximally tolerated dose for *2A/*2A (gene activity score 0)
is close to zero, as do the scarce data on tolerated doses in patients with gene activity score 0. For this reason, an alternative is advised.
There is a fairly good correlation between the residual DPD enzyme activity in peripheral blood mononuclear cells and the tolerated 5-FU or capecitabine dose. Therefore, if an alternative is not available, adjusting the dose according to the residual DPD enzyme activity in peripheral blood mononuclear cells is advised. This strategy has been shown to be feasible for capecitabine in two patients with genotype *2A/*2A. A patient with 0.5% of the normal DPD activity tolerated 0.8% of the normal capecitabine dose (150 mg every five days). A patient with undetectable DPD activity, tolerated 0.43% of the normal capecitabine dose (150 mg every five days with every third dose skipped).This is why this strategy is also recommended for tegafur in case an alternative is not possible.
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Rationale of
the therapeutic recommendation
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